Heterocyclic inhibitors of mek and methods of use thereof

ABSTRACT

Disclosed are compounds of the Formulas III and IV 
     
       
         
         
             
             
         
       
     
     and pharmaceutically acceptable salts and prodrugs thereof, wherein R 1 , R 2 , R 7 , R 8 , R 9 , and R 10  are as defined in the specification. Such compounds are MEK inhibitors and useful in the treatment of hyperproliferative diseases, such as cancer and inflammation, in mammals, and inflammatory conditions. Also disclosed are methods of using such compounds in the treatment of hyperproliferative diseases in mammals and pharmaceutical compositions containing such compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Divisional application of U.S. application Ser.No. 10/992,612, filed Nov. 18, 2004 and published as US 2005/0250782 onNov. 10, 2005, which claims the benefit of U.S. Provisional ApplicationSer. No. 60/523,270, filed Nov. 19, 2003, each of which is incorporatedherein in its entirety by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a series of novel heterocyclic compounds thatare useful in the treatment of hyperproliferative diseases, such ascancer and inflammation, in mammals. This invention also relates to amethod of using such compounds in the treatment of hyperproliferativediseases in mammals, especially humans, and to pharmaceuticalcompositions containing such compounds.

2. Description of the State of the Art

Cell signaling through growth factor receptors and protein kinases is animportant regulator of cell growth, proliferation and differentiation.In normal cell growth, growth factors, through receptor activation (i.e.PDGF or EGF and others), activate MAP kinase pathways. One of the mostimportant and most well understood MAP kinase pathways involved innormal and uncontrolled cell growth is the Ras/Raf kinase pathway.Active GTP-bound Ras results in the activation and indirectphosphorylation of Raf kinase. Raf then phosphorylates MEK1 and 2 on twoserine residues (S218 and S222 for MEK1 and S222 and S226 for MEK2) (Ahnet al, Methods in Enzymology, 2001, 332, 417-431). Activated MEK thenphosphorylates its only known substrates, the MAP kinases, ERK1 and 2.ERK phosphorylation by MEK occurs on Y204 and T202 for ERK1 and Y185 andT183 for ERK2 (Ahn et al., Methods in Enzymology, 2001, 332, 417-431).Phosphorylated ERK dimerizes and then translocates to the nucleus whereit accumulates (Khokhlatchev et al., Cell, 1998, 93, 605-615). In thenucleus, ERK is involved in several important cellular functions,including but not limited to nuclear transport, signal transduction, DNArepair, nucleosome assembly and translocation, and mRNA processing andtranslation (Ahn et al., Molecular Cell, 2000, 6, 1343-1354). Overall,treatment of cells with growth factors leads to the activation of ERK1and 2 which results in proliferation and, in some cases, differentiation(Lewis et al., Adv. Cancer Res., 1998, 74, 49-139).

In proliferative diseases, genetic mutations and/or overexpression ofthe growth factor receptors, downstream signaling proteins, or proteinkinases involved in the ERK kinase pathway lead to uncontrolled cellproliferation and, eventually, tumor formation. For example, somecancers contain mutations which result in the continuous activation ofthis pathway due to continuous production of growth factors. Othermutations can lead to defects in the deactivation of the activatedGTP-bound Ras complex, again resulting in activation of the MAP kinasepathway. Mutated, oncogenic forms of Ras are found in 50% of colonand >90% pancreatic cancers as well as many others types of cancers(Kohl et al, Science, 1993, 260, 1834-1837). Recently, bRaf mutationshave been identified in more than 60% of malignant melanoma (Davies, H.et al., Nature, 2002, 417, 949-954). These mutations in bRaf result in aconstitutively active MAP kinase cascade. Studies of primary tumorsamples and cell lines have also shown constitutive or overactivation ofthe MAP kinase pathway in cancers of pancreas, colon, lung, ovary andkidney (Hoshino, R. et al, Oncogene, 1999, 18, 813-822). Hence, there isa strong correlation between cancers and an overactive MAP kinasepathway resulting from genetic mutations.

As constitutive or overactivation of MAP kinase cascade plays a pivotalrole in cell proliferation and differentiation, inhibition of thispathway is believed to be beneficial in hyperproliferative diseases. MEKis a key player in this pathway as it is downstream of Ras and Raf.Additionally, it is an attractive therapeutic target because the onlyknown substrates for MEK phosphorylation are the MAP kinases, ERK1 and2. Inhibition of MEK has been shown to have potential therapeuticbenefit in several studies. For example, small molecule MEK inhibitorshave been shown to inhibit human tumor growth in nude mouse xenografts,(Sebolt-Leopold et al., Nature-Medicine, 1999, 5 (7), 810-816; Trachetet al., AACR Apr. 6-10, 2002, Poster #5426; Tecle, H., IBC 2^(nd)International Conference of Protein Kinases, Sep. 9-10, 2002), blockstatic allodynia in animals (WO 01/05390 published Jan. 25, 2001) andinhibit growth of acute myeloid leukemia cells (Milella et al., J. Clin.Invest., 2001, 108 (6), 851-859).

Small molecule inhibitors of MEK have been disclosed, including in U.S.Patent Publication Nos. 2003/0232869, 2004/0116710, and 2003/0216460,and U.S. patent application Ser. Nos. 10/654,580 and 10/929,295, each ofwhich is hereby incorporated by reference. At least fifteen additionalpatent applications have appeared in the last several years. See, forexample: U.S. Pat. No. 5,525,625; WO 98/43960; WO 99/01421; WO 99/01426;WO 00/41505; WO 00/42002; WO 00/42003; WO 00/41994; WO 00/42022; WO00/42029; WO 00/68201; WO 01/68619; WO 02/06213; WO 03/077914; and WO03/077855.

SUMMARY OF THE INVENTION

This invention provides for novel heterocyclic compounds, andpharmaceutically acceptable salts and prodrugs thereof that are usefulin the treatment of hyperproliferative diseases. Specifically, oneembodiment of the present invention relates to compounds of Formulas I-Vthat act as MEK inhibitors.

Accordingly, the present invention provides compounds of the FormulasI-V:

and pharmaceutically accepted salts, prodrugs and solvates thereof,wherein:

X is N or CR¹⁰;

Y is NR³, O, S, S(O), S(O)₂, C(O) or CH₂;

R¹, R², R⁸, and R⁹ are independently hydrogen, hydroxy, halogen, cyano,nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, azido, —SR¹¹, —OR³, —C(O)R³,—C(O)OR³, —NR⁴C(O)OR⁶, —OC(O)R³, —NR⁴SO₂R⁶, —SO₂NR³R⁴, —NR⁴C(O)R³,—C(O)NR³R⁴, —NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —NR³R⁴, C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl,—S(O)_(j)(C₁-C₆ alkyl), —S(O)_(j)(CR⁴R⁵)_(m)-aryl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl,—O(CR⁴R⁵)_(m)-aryl, —NR⁴(CR⁴R⁵)_(m)-aryl, —O(CR⁴R⁵)_(m)-heteroaryl,—NR⁴(CR⁴R⁵)_(m)-heteroaryl, —O(CR⁴R⁵)_(m)-heterocyclyl or—NR⁴(CR⁴R⁵)_(m)-heterocyclyl, wherein any of said alkyl, alkenyl,alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl portions are optionally substitutedwith one or more groups independently selected from oxo (with theproviso that it is not substituted on an aryl or heteroaryl), halogen,cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,—N³R⁴SO₂R⁶, —SO₂NR⁴, —C(O)R³, —C(O)OR³, —OC(O)R³, —NR⁴C(O)OR⁶,—NR⁴C(O)R³, —C(O)NR³R⁴, —NR³R⁴, —NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —OR³,aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl, and wherein said aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl or heterocyclylalkyl rings may be furthersubstituted with one or more groups selected from halogen, hydroxyl,cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl,C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, C₃-C₆heterocycloalkyl, NR³R⁴ and OR³;

R⁷ is hydrogen, trifluoromethyl, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, whereinany of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portionsare optionally substituted with one or more groups independentlyselected from oxo (with the proviso that it is not substituted on anaryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl,difluoromethyl, fluoromethyl, difluoromethoxy, trifluoromethoxy, azido,—NR¹¹SO₂R¹⁴, —SO₂NR¹¹R¹², —C(O)R¹¹, C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴,—NR¹¹C(O)R¹², —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴, —NR¹¹R¹²,—NR¹¹C(O)NR¹²R¹³, —NR¹¹C(NCN)NR¹¹R¹³, —OR¹¹, C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, and wherein saidaryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl orheterocyclylalkyl rings may be further substituted with one or moregroups selected from halogen, hydroxyl, cyano, nitro, azido,fluoromethyl, difluoromethyl, trifluoromethyl, C₁-C₄ alkyl, C₂-C₄alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, C₃-C₆ heterocycloalkyl, NR³R⁴and OR³;

R³ is hydrogen, trifluoromethyl, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, phosphateor an amino acid residue, wherein any of said alkyl, alkenyl, alkynyl,cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyland heterocyclylalkyl portions are optionally substituted with one ormore groups independently selected from oxo (with the proviso that it isnot substituted on an aryl or heteroaryl), halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴,—SO₂NR¹¹R¹², —C(O)R¹¹, C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴; —NR¹¹C(O)R¹²,—C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴, —NR¹¹R¹², —NR¹¹C(O)NR¹²R¹³,—NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl,

or R³ and R⁴ together with the atom to which they are attached form a 4to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein anyof said carbocyclic, heteroaryl or heterocyclic rings are optionallysubstituted with one or more groups independently selected from halogen,cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,—NR¹¹SO₂R¹¹, —SO₂NR¹¹R¹², —C(O)R¹¹, C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴,—NR¹¹C(O)R¹², —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴, —NR¹¹R¹²,—NR¹¹C(O)NR¹²R¹³, —NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl, heteroaryl,arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;

R⁴ and R⁵ independently are hydrogen or C₁-C₆ alkyl, or

R⁴ and R⁵ together with the atom to which they are attached form a 4 to10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein saidalkyl or any of said carbocyclic, heteroaryl and heterocyclic rings areoptionally substituted with one or more groups independently selectedfrom halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴, —SO₂NR¹¹R¹², —C(O)R¹¹, C(O)OR¹¹,—OC(O)R¹¹, —NR¹¹C(O)OR¹⁴, —NR¹¹C(O)R¹², —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴,—SO₂R¹⁴, —NR¹¹R¹², —NR¹¹C(O)NR¹²R¹³, —NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl;

R⁶ is trifluoromethyl, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, whereinany of said alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions areoptionally substituted with one or more groups independently selectedfrom oxo (with the proviso that it is not substituted on an aryl orheteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴, —SO₂NR¹¹R¹², —C(O)R¹¹, C(O)OR¹¹,—OC(O)R¹¹, —NR¹¹C(O)OR¹⁴, —NR¹¹C(O)R¹², —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴,—SO₂R¹⁴, —NR¹¹R¹², —NR¹¹C(O)NR¹¹R¹⁴, —NR¹¹C(NCN)NR¹¹R¹², —OR¹¹, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl;

wherein in Formulae I and V, R¹⁰ is hydrogen, hydroxy, halogen, cyano,nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —SR¹¹,—OR³, —C(O)R³, —C(O)OR³, —NR⁴C(O)OR⁶, —OC(O)R³, —NR⁴SO₂R⁶, —SO₂NR³R⁴,—NR⁴C(O)R³, —C(O)NR³R⁴, —NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —NR³R⁴, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀cycloalkylalkyl, —S(O)_(j)(C₁-C₆ alkyl), —S(O)_(j)(CR⁴R⁵)_(m)-aryl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl,heterocyclylalkyl, —O(CR⁴R⁵)_(m)-aryl, —NR⁴(CR⁴R⁵)_(m)-aryl,—O(CR⁴R⁵)_(m)-heteroaryl, —NR⁴(CR⁴R⁵)_(m)-heteroaryl,—O(CR⁴R⁵)_(m)-heterocyclyl or —NR⁴(CR⁴R⁵)_(m)-heterocyclyl, wherein anyof said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portionsare optionally substituted with one or more groups independentlyselected from oxo (with the proviso that it is not substituted on anaryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl,difluoromethoxy, trifluoromethoxy, azido, —NR⁴SO₂R⁶, —SO₂NR³R⁴, —C(O)R³,—C(O)OR³, —OC(O)R³, —NR⁴C(O)OR⁶, —NR⁴C(O)R³, —C(O)NR³R⁴, —NR³R⁴,—NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —OR³, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, and wherein saidaryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl orheterocyclylalkyl rings may be further substituted with one or moregroups selected from halogen, hydroxyl, cyano, nitro, azido,fluoromethyl, difluoromethyl, trifluoromethyl, C₁-C₄ alkyl, C₂-C₄alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, C₃-C₆ heterocycloalkyl, NR³R⁴and OR³;

and wherein in Formulae II and IV, each R¹⁰ is independently hydrogen,cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,—C(O)R³, —C(O)OR³, —SO₂NR³R⁴, —C(O)NR³R⁴, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl,C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl,—S(O)_(j)(C₁-C₆ alkyl), —S(O)_(j)(CR⁴R⁵)_(m)-aryl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, whereinany of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portionsare optionally substituted with one or more groups independentlyselected from oxo (with the proviso that it is not substituted on anaryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl,difluoromethoxy, trifluoromethoxy, azido, —NR⁴SO₂R⁶, —SO₂NR³R⁴, —C(O)R³,—C(O)OR³, —OC(O)R³, —NR⁴C(O)OR⁶, —NR⁴C(O)R³, —C(O)NR³R⁴, —NR³R⁴,—NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —OR³, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, and wherein saidaryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl orheterocyclylalkyl rings may be further substituted with one or moregroups selected from halogen, hydroxyl, cyano, nitro, azido,fluoromethyl, difluoromethyl, trifluoromethyl, C₁-C₄ alkyl, C₂-C₄alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, C₃-C₆ heterocycloalkyl, NR³R⁴and OR³;

R¹¹, R¹² and R¹³ independently are hydrogen, lower alkyl, lower alkenyl,aryl and arylalkyl, and R¹⁴ is lower alkyl, lower alkenyl, aryl andarylalkyl;

or any two of R¹¹, R¹², R¹³ or R¹⁴ together with the atom to which theyare attached form a 4 to 10 membered carbocyclic, heteroaryl orheterocyclic ring, wherein any of said alkyl, alkenyl, aryl, arylalkylcarbocyclic rings, heteroaryl rings or heterocyclic rings are optionallysubstituted with one or more groups independently selected from halogen,cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl;

W is heteroaryl, heterocyclyl, —C(O)OR³, —C(O)NR³R⁴, —C(O)NR⁴OR³,—C(O)R⁴OR³, —C(O)NR⁴SO₂R³, —C(O)(C₃-C₁₀ cycloalkyl), —C(O)(C₁-C₁₀alkyl), —C(O)(aryl), —C(O)(heteroaryl), —C(O)(heterocyclyl) or CR³OR³wherein any of said heteroaryl, heterocyclyl, —C(O)OR³, —C(O)NR³R⁴,—C(O)NR⁴OR³, —C(O)R⁴OR³, —C(O)NR⁴SO₂R³, —C(O)(C₃-C₁₀ cycloalkyl),—C(O)(C₁-C₁₀ alkyl), —C(O)(aryl), —C(O)(heteroaryl), —C(O)(heterocyclyl)and CR³OR³ are optionally substituted with one or more groupsindependently selected from halogen, cyano, nitro, azido, —NR³R⁴, —OR³,C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, cycloalkyl andheterocycloalkyl, wherein any of said C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl,C₂-C₁₀ alkynyl, cycloalkyl and heterocycloalkyl are optionallysubstituted with 1 or more groups independently selected from —NR³R⁴ and—OR;

m is 0, 1, 2, 3, 4 or 5; and

j is 0, 1 or 2.

In a further aspect, the present invention provides compositions thatinhibit MEK comprising one or more compounds of Formulas I-V.

The invention is also directed to pharmaceutically acceptable prodrugs,pharmaceutically active metabolites, and pharmaceutically acceptablesalts of compounds of Formula I-V. Methods of making the compounds ofFormula I-V are also described.

In a further aspect the present invention provides a method of using thecompounds of this invention as a medicament to treat diseases or medicalconditions mediated by MEK. For example, this invention provides amethod for treatment of a hyperproliferative disorder or an inflammatorycondition in a mammal comprising administrating to said mammal one ormore compounds of Formulas I-V or a pharmaceutically acceptable salt orprodrug thereof in an amount effective to treat said hyperproliferativedisorder.

In a further aspect the present invention provides treating orpreventing an MEK-mediated condition, comprising administering to ahuman or animal in need thereof a pharmaceutical composition comprisinga compound of Formula I-V or a pharmaceutically-acceptable salt or invivo cleavable prodrug thereof in an amount effective to treat orprevent said MEK-mediated condition.

The inventive compounds may further be used advantageously incombination with other known therapeutic agents.

The invention also relates to pharmaceutical compositions that inhibitMEK, comprising an effective amount of a compound selected fromcompounds of Formulas I-V or pharmaceutically acceptable prodrugs,pharmaceutically active metabolites, or pharmaceutically acceptablesalts thereof.

An additional aspect of the invention is the use of a compound ofFormula I, Formula II, Formula III, Formula IV or Formula V in thepreparation of a medicament for the treatment or prevention of a diseaseor medical condition mediated by MEK in a warm-blooded animal,preferably a mammal, more preferably a human, suffering from suchdisorder. More particularly, the invention includes the use of acompound of the invention in the preparation of a medicament for thetreatment or prevention of a hyperproliferative disorder or aninflammatory condition in a mammal.

Additional advantages and novel features of this invention shall be setforth in part in the description that follows, and in part will becomeapparent to those skilled in the art upon examination of the followingspecification or may be learned by the practice of the invention. Theadvantages of the invention may be realized and attained by means of theinstrumentalities, combinations, compositions, and methods particularlypointed out in the appended claims.

BRIEF DESCRIPTION OF THE FIGURES

The accompanying drawings, which are incorporated herein and form a partof the specification, illustrate non-limiting embodiments of the presentinvention, and together with the description, serve to explain theprinciples of the invention.

In the Figures:

FIG. 1 shows a reaction scheme for the synthesis of compounds 5-7.

FIG. 2 shows a reaction scheme for the synthesis of compounds 7 and 11.

FIG. 3 shows a reaction scheme for the synthesis of compounds 14 and 15.

FIG. 4 shows a reaction scheme for the synthesis of compound 16.

FIG. 5 shows a reaction scheme for the synthesis of compounds 18-23.

FIG. 6 shows a reaction scheme for the synthesis of compounds 25-27.

FIG. 7 shows a reaction scheme for the synthesis of compound 33.

FIG. 8 shows a reaction scheme for the synthesis of compounds 34-36.

FIG. 9 shows a reaction scheme for the synthesis of compound 40.

FIG. 10 shows a reaction scheme for the synthesis of compounds 42-46.

FIG. 11 shows a reaction scheme for the synthesis of compound 47.

FIG. 12 shows a reaction scheme for the synthesis of compound 48.

FIG. 13 shows a reaction scheme for the synthesis of compound 49.

FIG. 14 shows a reaction scheme for the synthesis of compound 51.

FIG. 15 shows a reaction scheme for the synthesis of compounds 54-57.

FIG. 16 shows a reaction scheme for the synthesis of compounds 54 and56.

FIG. 17 shows a reaction scheme for an alternate synthesis of compounds54-57.

FIG. 18 shows a reaction scheme for the synthesis of compounds 54 and60.

FIG. 19 shows a reaction scheme for the synthesis of compounds 62-64.

FIG. 20 shows a reaction scheme for the synthesis of compound 63.

FIG. 21 shows a reaction scheme for the synthesis of compounds 61 and66.

FIG. 22 shows a reaction scheme for an alternate synthesis of compound61.

FIG. 23 shows a reaction scheme for the synthesis of compound 65.

FIG. 24 shows a reaction scheme for the synthesis of compounds 65 and70.

FIG. 25 shows a reaction scheme for an alternate synthesis of compound65.

FIG. 26 shows a reaction scheme for an alternate synthesis of compound65.

FIG. 27 shows a reaction scheme for an alternate synthesis of compound65.

FIG. 28 shows a reaction scheme for an alternate synthesis of compound61.

FIG. 29 shows a reaction scheme for the synthesis of compound 80.

FIG. 30 shows a reaction scheme for the synthesis of compounds 81 and82.

FIG. 31 shows a reaction scheme for the synthesis of compounds 83 and84.

FIG. 32 shows a reaction scheme for the synthesis of compound 85.

FIG. 33 shows a reaction scheme for the synthesis of compounds 86-91.

FIG. 34 shows a reaction scheme for the synthesis of compounds 92 and93.

DETAILED DESCRIPTION OF THE INVENTION

The inventive compounds of the Formulas I-V and the pharmaceuticallyacceptable salts and prodrugs thereof of this invention are useful inthe treatment of hyperproliferative diseases. Specifically, one aspectthe present invention relates to compounds of Formula I-V that act asMEK inhibitors. In general, one aspect of the invention relates tocompounds having the general Formula I:

and pharmaceutically accepted salts, prodrugs and solvates thereof,where:

X is N or CR¹⁰;

Y is NR³, O, S, S(O), S(O)₂, C(O) or CH₂;

R¹, R², R⁸, R⁹ and R¹⁰ are independently hydrogen, hydroxy, halogen,cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl,fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, —SR11, —OR³,—C(O)R³, —C(O)OR³, —NR⁴C(O)OR⁶, —OC(O)R³, —NR⁴SO₂R⁶, —SO₂NR³R⁴,—NR⁴C(O)R³, —C(O)NR³R⁴, —NR⁵C(O)NR³NR⁴, —NR⁵C(NCN)NR³NR⁴, —NR³R⁴, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀cycloalkylalkyl, —S(O)_(j)(C₁-C₆ alkyl), —S(O)_(j)(CR⁴R⁵)_(m)-aryl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl,heterocyclylalkyl, —O(CR⁴R⁵)_(m)-aryl, —NR⁴(CR⁴R⁵)_(m)-aryl,—O(CR⁴R⁵)_(m)-heteroaryl, —NR⁴(CR⁴R⁵)_(m)-heteroaryl,—O(CR⁴R⁵)_(m)-heterocyclyl or —NR⁴(CR⁴R⁵)_(m)-heterocyclyl, wherein anyof said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portionsare optionally substituted with one or more groups independentlyselected from oxo (with the proviso that it is not substituted on anaryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl,difluoromethoxy, trifluoromethoxy, azido, —NR³NR⁴SO₂R⁶, —SO₂NR³NR⁴,—C(O)R³, —C(O)OR³, —OC(O)R³, —NR⁴C(O)OR⁶, —NR⁴C(O)R³, —C(O)NR³R⁴,—NR³R⁴, —NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —OR³, aryl, heteroaryl,arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, andwherein said aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclylor heterocyclylalkyl rings may be further substituted with one or moregroups selected from halogen, hydroxyl, cyano, nitro, azido,fluoromethyl, difluoromethyl, trifluoromethyl, C₁-C₄ alkyl, C₂-C₄alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, C₃-C₆ heterocycloalkyl, NR³R⁴and OR³;

R⁷ is hydrogen, trifluoromethyl, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, whereinany of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portionsare optionally substituted with one or more groups independentlyselected from oxo (with the proviso that it is not substituted on anaryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl,difluoromethyl, fluoromethyl, difluoromethoxy, trifluoromethoxy, azido,—NR¹¹SO₂R¹⁴, —SO₂NR¹¹R¹², —C(O)R¹¹, C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴,—NR¹¹C(O)R¹², —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴, —NR¹¹R¹²,—NR¹¹C(O)NR¹²R¹³, —NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, and wherein saidaryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl orheterocyclylalkyl rings may be further substituted with one or moregroups selected from halogen, hydroxyl, cyano, nitro, azido,fluoromethyl, difluoromethyl, trifluoromethyl, C₁-C₄ alkyl, C₂-C₄alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, C₃-C₆ heterocycloalkyl, NR³R⁴and OR³;

R³ is hydrogen, trifluoromethyl, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, phosphateor an amino acid residue, wherein any of said alkyl, alkenyl, alkynyl,cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyland heterocyclylalkyl portions are optionally substituted with one ormore groups independently selected from oxo (with the proviso that it isnot substituted on an aryl or heteroaryl), halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴,—SO₂NR¹¹R¹², —C(O)R¹¹, C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴, —NR¹¹C(O)R¹²,—C(O)NR¹¹R¹⁴, —SR¹¹, —S(O)R¹⁴, —SO₂R¹¹, —NR¹¹R¹², —NR¹¹C(O)NR¹²R¹³,—NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl,

or R³ and R⁴ together with the atom to which they are attached form a 4to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein anyof said carbocyclic, heteroaryl or heterocyclic rings are optionallysubstituted with one or more groups independently selected from halogen,cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,—NR¹¹SO₂R¹⁴, —SO₂NR¹¹R¹², —C(O)R¹¹, C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴,—NR¹¹C(O)R¹², —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴, —NR¹¹R¹²,—NR¹¹C(O)NR¹²R¹³, —NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl, heteroaryl,arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;

R⁴ and R⁵ independently are hydrogen or C₁-C₆ alkyl, or

R⁴ and R⁵ together with the atom to which they are attached form a 4 to10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein saidalkyl or any of said carbocyclic, heteroaryl and heterocyclic rings areoptionally substituted with one or more groups independently selectedfrom halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴, —SO₂NR¹¹R¹², —C(O)R¹¹, C(O)OR¹¹,—OC(O)R¹¹, —NR¹¹C(O)OR¹⁴, —NR¹¹C(O)R¹², —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴,—SO₂R¹⁴, —NR¹¹R¹², —NR¹¹C(O)NR¹²R¹³, —NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl;

R⁶ is trifluoromethyl, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, whereinany of said alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions areoptionally substituted with one or more groups independently selectedfrom oxo (with the proviso that it is not substituted on an aryl orheteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴, —SO₂NR¹¹R¹², —C(O)R¹¹, C(O)OR¹¹,—OC(O)R¹¹, —NR¹¹C(O)OR¹⁴, —NR¹¹C(O)R¹², —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴,—SO₂R¹⁴, —NR¹¹R¹², —NR¹¹C(O)NR¹²R¹³, —NR¹¹C(NCN)NR¹¹R¹², —OR¹¹, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl;

R¹¹, R¹² and R¹³ independently are hydrogen, lower alkyl, lower alkenyl,aryl and arylalkyl, and R¹⁴ is lower alkyl, lower alkenyl, aryl andarylalkyl;

or any two of R¹¹, R¹², R¹³ or R¹⁴ together with the atom to which theyare attached form a 4 to 10 membered carbocyclic, heteroaryl orheterocyclic ring, wherein any of said alkyl, alkenyl, aryl, arylalkylcarbocyclic rings, heteroaryl rings or heterocyclic rings are optionallysubstituted with one or more groups independently selected from halogen,cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl;

W is heteroaryl, heterocyclyl, —C(O)OR³, —C(O)NR³R⁴, —C(O)NR⁴OR³,—C(O)R⁴OR³, —C(O)NR⁴SO₂R³, —C(O)(C₃-C₁₀ cycloalkyl), —C(O)(C₁-C₁₀alkyl), —C(O)(aryl), —C(O)(heteroaryl), —C(O)(heterocyclyl) or CR³OR³wherein any of said heteroaryl, heterocyclyl, —C(O)OR³, —C(O)NR³R⁴,—C(O)NR⁴OR³, —C(O)R⁴OR³, —C(O)NR⁴SO₂R³, —C(O)(C₃-C₁₀ cycloalkyl),—C(O)(C₁-C₁₀ alkyl), —C(O)(aryl), —C(O)(heteroaryl), —C(O)(heterocyclyl)and CR³OR³ are optionally substituted with one or more groupsindependently selected from halogen, cyano, nitro, azido, —NR³R⁴, —OR³,C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, cycloalkyl andheterocycloalkyl, wherein any of said C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl,C₂-C₁₀ alkynyl, cycloalkyl and heterocycloalkyl are optionallysubstituted with 1 or more groups independently selected from —NR³R⁴ and—OR;

m is 0, 1, 2, 3, 4 or 5; and

j is 0, 1 or 2.

In one embodiment, W is selected from

FIGS. 1-3, 6, 7 and 10-14 show non-limiting examples of the synthesis ofcompounds of this invention having the general Formula I.

In addition to compounds of the general Formula I, this inventionfurther includes compounds of the general Formula II:

and pharmaceutically accepted salts, prodrugs and solvates thereof,where:

where R¹, R², R⁸ and R⁹ are independently hydrogen, halogen, cyano,nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, azido, —SR¹¹, —OR³, —C(O)R³,—C(O)OR³, —NR⁴C(O)OR⁶, —OC(O)R³, —NR⁴SO₂R⁶, —SO₂NR³R⁴, —NR⁴C(O)R³,—C(O)NR³R⁴, —NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —NR³R⁴, C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl,—S(O)_(j)(C₁-C₆ alkyl), —S(O)_(j)(CR⁴R⁵)_(m)-aryl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl,—O(CR⁴R⁵)_(m)-aryl, —NR⁴(CR⁴R⁵)_(m)-aryl, —O(CR⁴R⁵)_(m)-heteroaryl,—NR⁴(CR⁴R⁵)_(m)-heteroaryl, —O(CR⁴R⁵)_(m)-heterocyclyl or—NR⁴(CR⁴R⁵)_(m)-heterocyclyl, wherein any of said alkyl, alkenyl,alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl portions are optionally substitutedwith one or more groups independently selected from oxo (with theproviso that it is not substituted on an aryl or heteroaryl), halogen,cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,—NR⁴SO₂R⁶, —SO₂NR³ 459R⁴, —C(O)R³, —C(O)OR³, —OC(O)R³, —NR⁴C(O)OR⁶,—NR⁴C(O)R³, —C(O)NR³R⁴, —NR³R⁴, —NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —OR³,aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl, and wherein said aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl or heterocyclylalkyl rings may be furthersubstituted with one or more groups selected from halogen, hydroxyl,cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl,C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, C₃-C₆heterocycloalkyl, NR³R⁴ and OR³;

R⁷ is hydrogen, trifluoromethyl, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, whereinany of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portionsare optionally substituted with one or more groups independentlyselected from oxo (with the proviso that it is not substituted on anaryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl,difluoromethyl, fluoromethyl, difluoromethoxy, trifluoromethoxy, azido,—NR¹¹SO₂R¹⁴, —SO₂NR¹¹R¹², —C(O)R¹¹, C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴,—NR¹¹C(O)R¹², —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴, —NR¹¹R¹²,—NR¹¹C(O)NR¹²R¹³, —NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, and wherein saidaryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl orheterocyclylalkyl rings may be further substituted with one or moregroups selected from halogen, hydroxyl, cyano, nitro, azido,fluoromethyl, difluoromethyl, trifluoromethyl, C₁-C₄ alkyl, C₂-C₄alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, C₃-C₆ heterocycloalkyl, NR³R⁴and OR³;

each R¹⁰ is independently hydrogen, cyano, nitro, trifluoromethyl,difluoromethoxy, trifluoromethoxy, azido, —C(O)R³, —C(O)OR³, —SO₂NR³R⁴,—C(O)NR³R⁴, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀cycloalkyl, C₃-C₁₀ cycloalkylalkyl, —S(O)_(j)(C₁-C₆ alkyl),—S(O)_(j)(CR⁴R⁵)_(m)-aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl or heterocyclylalkyl, wherein any of said alkyl, alkenyl,alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl portions are optionally substitutedwith one or more groups independently selected from oxo (with theproviso that it is not substituted on an aryl or heteroaryl), halogen,cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,—NR⁴SO₂R⁶, —SO₂NR³R⁴, —C(O)R³, —C(O)OR³, —OC(O)R³, —NR⁴C(O)OR⁶,—NR⁴C(O)R³, —C(O)NR³R⁴, —NR³R⁴, —NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —OR³,aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl, and wherein said aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl or heterocyclylalkyl rings may be furthersubstituted with one or more groups selected from halogen, hydroxyl,cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl,C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, C₃-C₆heterocycloalkyl, NR³R⁴ and OR³;

R³ is hydrogen, trifluoromethyl, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, phosphateor an amino acid residue, wherein any of said alkyl, alkenyl, alkynyl,cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyland heterocyclylalkyl portions are optionally substituted with one ormore groups independently selected from oxo (with the proviso that it isnot substituted on an aryl or heteroaryl), halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴,—SO₂NR¹¹R¹², —C(O)R¹¹, C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴, —NR¹¹C(O)R¹²,—C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴, —NR¹¹R¹², —NR¹¹C(O)NR¹²R¹³.—NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl,

or R³ and R⁴ together with the atom to which they are attached form a 4to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein anyof said carbocyclic, heteroaryl or heterocyclic rings are optionallysubstituted with one or more groups independently selected from halogen,cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,—NR¹¹SO₂R¹⁴, —SO₂NR¹¹R¹², —C(O)R¹¹, C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴,—NR¹¹C(O)R¹², —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴, —NR¹¹R¹²,—NR¹¹C(O)NR¹²R¹³, —NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl, heteroaryl,arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;

R⁴ and R⁵ independently are hydrogen or C₁-C₆ alkyl, or

R⁴ and R⁵ together with the atom to which they are attached form a 4 to10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein saidalkyl or any of said carbocyclic, heteroaryl and heterocyclic rings areoptionally substituted with one or more groups independently selectedfrom halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴, —SO₂NR¹¹R¹², —C(O)R¹¹, C(O)OR¹¹,—OC(O)R¹¹, —NR¹¹C(O)OR¹⁴, —NR¹¹C(O)R¹², —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴,—SO₂R¹⁴, —NR¹¹R¹², —NR¹¹C(O)NR¹²R¹³, —NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl;

R⁶ is trifluoromethyl, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, whereinany of said alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions areoptionally substituted with one or more groups independently selectedfrom oxo (with the proviso that it is not substituted on an aryl orheteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴, —SO₂NR¹¹R¹², —C(O)R¹¹, C(O)OR¹¹,—OC(O)R¹¹, —NR¹¹C(O)OR¹⁴, —NR¹¹C(O)R¹², —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴,—SO₂R¹⁴, —NR¹¹R¹², —NR¹¹C(O)NR¹²R¹³, —NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl;

R¹¹, R¹² and R¹³ independently are hydrogen, lower alkyl, lower alkenyl,aryl and arylalkyl, and R¹⁴ is lower alkyl, lower alkenyl, aryl andarylalkyl;

or any two of R¹¹, R¹², R¹³ or R¹⁴ together with the atom to which theyare attached form a 4 to 10 membered carbocyclic, heteroaryl orheterocyclic ring, wherein any of said alkyl, alkenyl, aryl, arylalkylcarbocyclic rings, heteroaryl rings or heterocyclic rings are optionallysubstituted with one or more groups independently selected from halogen,cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl;

m is 0, 1, 2, 3, 4 or 5;

n is 1 or 2; and

j is 0, 1 or 2.

FIG. 5 shows non-limiting examples of the synthesis of compounds of thisinvention having the general Formula II.

In another embodiment, this invention relates to compounds of thegeneral Formula III:

and pharmaceutically accepted salts, prodrugs and solvates thereof,where:

R¹, R², R⁸ and each R⁹ are independently hydrogen, halogen, cyano,nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, azido, —SR¹¹, —OR³, —C(O)R³,—C(O)OR³, —NR⁴C(O)OR⁶, —OC(O)R³, —NR⁴SO₂R⁶, —SO₂NR³R⁴, —NR⁴C(O)R³,—C(O)NR³R⁴, —NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —NR³R⁴, C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl,—S(O)_(j)(C₁-C₆ alkyl), —S(O)_(j)(CR⁴R⁵)_(m)-aryl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl,—O(CR⁴R⁵)_(m)-aryl, —NR⁴(CR⁴R⁵)_(m)-aryl, —O(CR⁴R⁵)_(m)-heteroaryl,—NR⁴(CR⁴R⁵)_(m)-heteroaryl, —O(CR⁴R⁵)_(m)-heterocyclyl or—NR⁴(CR⁴R⁵)_(m)-heterocyclyl, wherein any of said alkyl, alkenyl,alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl portions are optionally substitutedwith one or more groups independently selected from oxo (with theproviso that it is not substituted on an aryl or heteroaryl), halogen,cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,—NR⁴SO₂R⁶, —SO₂NR³R⁴, —C(O)R³, —C(O)OR³, —OC(O)R³, —NR⁴C(O)OR⁶,—NR⁴C(O)R³, —C(O)NR³R⁴, —NR³R⁴, —NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —OR³,aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl, and wherein said aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl or heterocyclylalkyl rings may be furthersubstituted with one or more groups selected from halogen, hydroxyl,cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl,C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, C₃-C₆heterocycloalkyl, NR³R⁴ and OR³;

R⁷ is hydrogen, trifluoromethyl, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, whereinany of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portionsare optionally substituted with one or more groups independentlyselected from oxo (with the proviso that it is not substituted on anaryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl,difluoromethyl, fluoromethyl, difluoromethoxy, trifluoromethoxy, azido,—NR¹¹SO₂R¹⁴, —SO₂NR¹¹R¹², —C(O)R¹¹, C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴,—NR¹¹C(O)R¹², —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴, —NR¹¹R¹²,—NR¹¹C(O)NR¹²R¹³, —NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, and wherein saidaryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl orheterocyclylalkyl rings may be further substituted with one or moregroups selected from halogen, hydroxyl, cyano, nitro, azido,fluoromethyl, difluoromethyl, trifluoromethyl, C₁-C₄ alkyl, C₂-C₄alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, C₃-C₆ heterocycloalkyl, NR³R⁴and OR³;

R³ is hydrogen, trifluoromethyl, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, phosphateor an amino acid residue, wherein any of said alkyl, alkenyl, alkynyl,cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyland heterocyclylalkyl portions are optionally substituted with one ormore groups independently selected from oxo (with the proviso that it isnot substituted on an aryl or heteroaryl), halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴,—SO₂NR¹¹R¹², —C(O)R¹¹, C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴, —NR¹¹C(O)R¹²,—C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹¹, —SO₂R¹⁴, —NR¹¹R¹², —NR¹¹C(O)NR¹²R¹³,—NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl,

or R³ and R⁴ together with the atom to which they are attached form a 4to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein anyof said carbocyclic, heteroaryl or heterocyclic rings are optionallysubstituted with one or more groups independently selected from halogen,cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,—NR¹¹SO₂R¹¹, —SO₂NR¹¹R¹², —C(O)R¹¹, C(O)OR¹¹, —OC(O)R¹³, —NR¹¹C(O)OR¹⁴,—NR¹¹C(O)R¹², —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴, —NR¹¹R¹²,—NR¹¹C(O)NR¹²R¹³, —NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl, heteroaryl,arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;

R⁴ and R⁵ independently are hydrogen or C₁-C₆ alkyl, or

R⁴ and R⁵ together with the atom to which they are attached form a 4 to10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein saidalkyl or any of said carbocyclic, heteroaryl and heterocyclic rings areoptionally substituted with one or more groups independently selectedfrom halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴, —SO₂NR¹¹R¹², —C(O)R¹¹, C(O)OR¹¹,—OC(O)R¹¹, —NR¹¹C(O)OR¹⁴, —NR¹¹C(O)R¹², —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴,—SO₂R¹⁴, —NR¹¹R¹², —NR¹¹C(O)NR¹²R¹³, —NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl;

R⁶ is trifluoromethyl, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, whereinany of said alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions areoptionally substituted with one or more groups independently selectedfrom oxo (with the proviso that it is not substituted on an aryl orheteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴, —SO₂NR¹¹R¹², —C(O)R¹¹, C(O)OR¹¹,—OC(O)R¹¹, —NR¹¹C(O)OR¹⁴, —NR¹¹C(O)R¹², —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴,—SO₂R¹⁴, —NR¹¹R¹², —NR¹¹C(O)NR¹²R¹³, —NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl;

R¹¹, R¹² and R¹³ independently are hydrogen, lower alkyl, lower alkenyl,aryl and arylalkyl, and

R¹⁴ is lower alkyl, lower alkenyl, aryl and arylalkyl;

or any two of R¹¹, R¹², R¹³ or R¹⁴ together with the atom to which theyare attached form a 4 to 10 membered carbocyclic, heteroaryl orheterocyclic ring, wherein any of said alkyl, alkenyl, aryl, arylalkylcarbocyclic rings, heteroaryl rings or heterocyclic rings are optionallysubstituted with one or more groups independently selected from halogen,cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl;

m is 0, 1, 2, 3, 4 or 5; and

j is 0, 1 or 2.

FIGS. 8 and 9 show non-limiting examples of the synthesis of compoundsof this invention having the general Formula III.

In another embodiment, this invention relates to compounds of thegeneral Formula IV:

and pharmaceutically accepted salts, prodrugs and solvates thereof,where:

R¹, R², R⁸ and R⁹ are independently hydrogen, halogen, cyano, nitro,trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, azido, —SR¹¹, —OR³, —C(O)R³,—C(O)OR³, —NR⁴C(O)OR⁶, —OC(O)R³, —NR⁴SO₂R⁶, —SO₂NR³R⁴, —NR⁴C(O)R³,—C(O)NR³R⁴, —NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —NR³R⁴, C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl,—S(O)_(j)(C₁-C₆ alkyl), —S(O)_(j)(CR⁴R⁵)_(m)-aryl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl,—O(CR⁴R⁵)_(m)-aryl, —NR⁴(CR⁴R⁵)_(m)-aryl, —O(CR⁴R⁵)_(m)-heteroaryl,—NR⁴(CR⁴R⁵)_(m)-heteroaryl, —O(CR⁴R⁵)_(m)-heterocyclyl or—NR⁴(CR⁴R⁵)_(m)-heterocyclyl, wherein any of said alkyl, alkenyl,alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl portions are optionally substitutedwith one or more groups independently selected from oxo (with theproviso that it is not substituted on an aryl or heteroaryl), halogen,cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,—NR⁴SO₂R⁶, —SO₂NR³R⁴, —C(O)R³, —C(O)OR³, —OC(O)R³, —NR⁴C(O)OR⁶,—NR⁴C(O)R³, —C(O)NR³R⁴, —NR³R⁴, —NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —OR³,aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl, and wherein said aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl or heterocyclylalkyl rings may be furthersubstituted with one or more groups selected from halogen, hydroxyl,cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl,C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, C₃-C₆heterocycloalkyl, NR³R⁴ and OR³;

each R⁷ is hydrogen, trifluoromethyl, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl,C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, orheterocyclylalkyl, wherein any of said alkyl, alkenyl, alkynyl,cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyland heterocyclylalkyl portions are optionally substituted with one ormore groups independently selected from oxo (with the proviso that it isnot substituted on an aryl or heteroaryl), halogen, cyano, nitro,trifluoromethyl, difluoromethyl, fluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴, —SO₂NR¹¹R¹², —C(O)R¹¹, C(O)OR¹¹,—OC(O)R¹¹, —NR¹¹C(O)OR¹⁴, —NR¹¹C(O)R¹², —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴,—SO₂R¹⁴, —NR¹¹R¹², —NR¹¹C(O)NR¹²R¹³, —NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl, and wherein said aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl or heterocyclylalkyl rings may be furthersubstituted with one or more groups selected from halogen, hydroxyl,cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl,C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, C₃-C₆heterocycloalkyl, NR³R⁴ and OR³;

each R¹⁰ is independently hydrogen, cyano, nitro, trifluoromethyl,difluoromethoxy, trifluoromethoxy, azido, —C(O)R³, —C(O)OR³, —SO₂NR³R⁴,—C(O)NR³R⁴, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀cycloalkyl, C₃-C₁₀ cycloalkylalkyl, —S(O)_(j)(C₁-C₆ alkyl),—S(O)_(j)(CR⁴R⁵)_(m)-aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl or heterocyclylalkyl, wherein any of said alkyl, alkenyl,alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl portions are optionally substitutedwith one or more groups independently selected from oxo (with theproviso that it is not substituted on an aryl or heteroaryl), halogen,cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,—NR⁴SO₂R⁶, —SO₂NR³R⁴, —C(O)R³, —C(O)OR³, —OC(O)R³, —NR⁴C(O)OR⁶,—NR⁴C(O)R³, —C(O)NR³R⁴, —NR³R⁴, —NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —OR³,aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl, and wherein said aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl or heterocyclylalkyl rings may be furthersubstituted with one or more groups selected from halogen, hydroxyl,cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl,C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, C₃-C₆heterocycloalkyl, NR³R⁴ and OR³;

R³ is hydrogen, trifluoromethyl, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, phosphateor an amino acid residue, wherein any of said alkyl, alkenyl, alkynyl,cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyland heterocyclylalkyl portions are optionally substituted with one ormore groups independently selected from oxo (with the proviso that it isnot substituted on an aryl or heteroaryl), halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴,—SO₂NR¹¹R¹², —C(O)R¹¹, C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹²R¹³,—NR¹¹C(O)R¹², —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴, —NR¹¹R¹²,—NR¹¹C(O)NR¹²R¹³, —NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl, heteroaryl,arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl,

or R³ and R⁴ together with the atom to which they are attached form a 4to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein anyof said carbocyclic, heteroaryl or heterocyclic rings are optionallysubstituted with one or more groups independently selected from halogen,cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,—NR¹¹SO₂R¹⁴, —SO₂NR¹¹R¹², —C(O)R¹¹, C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴,—NR¹¹C(O)R¹², —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴, —NR¹¹R¹²,—NR¹¹C(O)NR¹²R¹³, —NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl, heteroaryl,arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;

R⁴ and R⁵ independently are hydrogen or C₁-C₆ alkyl, or

R⁴ and R⁵ together with the atom to which they are attached form a 4 to10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein saidalkyl or any of said carbocyclic, heteroaryl and heterocyclic rings areoptionally substituted with one or more groups independently selectedfrom halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴, —SO₂NR¹¹R¹², —C(O)R¹¹, C(O)OR¹¹,—OC(O)R¹¹, —NR¹¹C(O)OR¹⁴, —NR¹¹C(O)R¹², —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴,—SO₂R¹⁴, —NR¹¹R¹², —NR¹¹C(O)NR¹²R¹³, —NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl;

R⁶ is trifluoromethyl, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, whereinany of said alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions areoptionally substituted with one or more groups independently selectedfrom oxo (with the proviso that it is not substituted on an aryl orheteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴, —SO₂NR¹¹R¹², —C(O)R¹¹, C(O)OR¹¹,—OC(O)R¹¹, —NR¹¹C(O)OR¹⁴, —NR¹¹C(O)R¹², —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴,—SO₂R¹⁴, —NR¹¹R¹², —NR¹¹C(O)NR¹¹R¹², —NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl;

R¹¹, R¹² and R¹³ independently are hydrogen, lower alkyl, lower alkenyl,aryl and arylalkyl, and

R¹⁴ is lower alkyl, lower alkenyl, aryl and arylalkyl;

or any two of R¹¹, R¹², R¹³ or R¹⁴ together with the atom to which theyare attached form a 4 to 10 membered carbocyclic, heteroaryl orheterocyclic ring, wherein any of said alkyl, alkenyl, aryl, arylalkylcarbocyclic rings, heteroaryl rings or heterocyclic rings are optionallysubstituted with one or more groups independently selected from halogen,cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl;

m is 0, 1, 2, 3, 4 or 5; and

j is 0, 1 or 2.

FIG. 5 shows non-limiting examples of the synthesis of compounds of thisinvention having the general Formula IV.

In another embodiment, this invention relates to compounds of thegeneral Formula V:

and pharmaceutically accepted salts, prodrugs and solvates thereof,where:

X is N or CR¹⁰;

R¹, R², R⁸, R⁹ and R¹⁰ are independently hydrogen, halogen, cyano,nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, azido, —SR¹¹, —OR³, —C(O)R³,—C(O)OR³, —NR⁴C(O)OR⁶, —OC(O)R³, —NR⁴SO₂R⁶, —SO₂N³R⁴, —NR⁴C(O)R³,—C(O)NR³R⁴, —NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —NR³R⁴, C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl,—S(O)_(j)(C₁-C₆ alkyl), —S(O)_(j)(CR⁴R⁵)_(m)-aryl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl,—O(CR⁴R⁵)_(m)-aryl, —NR⁴(CR⁴R⁵)_(m)-aryl, —O(CR⁴R⁵)_(m)-heteroaryl,—NR⁴(CR⁴R⁵)_(m)-heteroaryl, —O(CR⁴R⁵)_(m)-heterocyclyl or—NR⁴(CR⁴R⁵)_(m)-heterocyclyl, wherein any of said alkyl, alkenyl,alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl portions are optionally substitutedwith one or more groups independently selected from oxo (with theproviso that it is not substituted on an aryl or heteroaryl), halogen,cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,—NR⁴SO₂R⁶, —SO₂NR³R⁴, —C(O)R³, —C(O)OR³, —OC(O)R³, —NR⁴C(O)OR⁶,—NR⁴C(O)R³, —C(O)NR³R⁴, —NR³R⁴, —NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —OR³,aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl, and wherein said aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl or heterocyclylalkyl rings may be furthersubstituted with one or more groups selected from halogen, hydroxyl,cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl,C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, C₃-C₆heterocycloalkyl, NR³R⁴ and OR³;

R⁷ is hydrogen, trifluoromethyl, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, whereinany of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portionsare optionally substituted with one or more groups independentlyselected from oxo (with the proviso that it is not substituted on anaryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl,difluoromethyl, fluoromethyl, difluoromethoxy, trifluoromethoxy, azido,—NR¹¹SO₂R¹⁴, —SO₂NR¹¹R¹², —C(O)R¹¹, C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴,—NR¹¹C(O)R¹², —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹¹, —NR¹¹R¹²,—NR¹¹C(O)NR¹²R¹³, —NR¹¹C(NCN)NR¹³R¹³, —OR¹¹, C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, and wherein saidaryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl orheterocyclylalkyl rings may be further substituted with one or moregroups selected from halogen, hydroxyl, cyano, nitro, azido,fluoromethyl, difluoromethyl, trifluoromethyl, C₁-C₄ alkyl, C₂-C₄alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, C₃-C₆ heterocycloalkyl, NR³R⁴and OR³;

R³ is hydrogen, trifluoromethyl, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, phosphateor an amino acid residue, wherein any of said alkyl, alkenyl, alkynyl,cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyland heterocyclylalkyl portions are optionally substituted with one ormore groups independently selected from oxo (with the proviso that it isnot substituted on an aryl or heteroaryl), halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴,—SO₂NR¹¹R¹², —C(O)R¹¹, C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴, —NR¹¹C(O)R¹²,—C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴, —NR¹¹R¹², —NR¹¹C(O)NR¹²R¹³,—NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl,

or R³ and R⁴ together with the atom to which they are attached form a 4to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein anyof said carbocyclic, heteroaryl or heterocyclic rings are optionallysubstituted with one or more groups independently selected from halogen,cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,—NR¹¹SO₂R¹⁴, —SO₂NR¹¹R¹², —C(O)R¹¹, C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴,—NR¹¹C(O)R¹², —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴, —NR¹¹R¹²,—NR¹¹C(O)NR¹²R¹³, —NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl, heteroaryl,arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;

R⁴ and R⁵ independently are hydrogen or C₁-C₆ alkyl, or

R⁴ and R⁵ together with the atom to which they are attached form a 4 to10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein saidalkyl or any of said carbocyclic, heteroaryl and heterocyclic rings areoptionally substituted with one or more groups independently selectedfrom halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴, —SO₂NR¹¹R¹², —C(O)R¹¹, C(O)OR¹¹,—OC(O)R¹¹, —NR¹¹C(O)OR¹⁴, —NR¹¹C(O)R¹², —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴,—SO₂R¹⁴, —NR¹¹R¹², —NR¹¹C(O)NR¹²R¹³, —NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl;

R⁶ is trifluoromethyl, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, whereinany of said alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions areoptionally substituted with one or more groups independently selectedfrom oxo (with the proviso that it is not substituted on an aryl orheteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴, —SO₂NR¹¹R¹², —C(O)R¹¹, C(O)OR¹¹,—OC(O)R¹¹, —NR¹¹C(O)OR¹⁴, —NR¹¹C(O)R¹², —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴,—SO₂R¹⁴, —NR¹¹R¹², —NR¹¹C(O)NR¹²R¹³, —NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl;

R¹¹, R¹² and R¹³ independently are hydrogen, lower alkyl, lower alkenyl,aryl and arylalkyl, and R¹⁴ is lower alkyl, lower alkenyl, aryl andarylalkyl;

or any two of R¹¹, R¹², R¹³ or R¹⁴ together with the atom to which theyare attached form a 4 to 10 membered carbocyclic, heteroaryl orheterocyclic ring, wherein any of said alkyl, alkenyl, aryl, arylalkylcarbocyclic rings, heteroaryl rings or heterocyclic rings are optionallysubstituted with one or more groups independently selected from halogen,cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl;

W is heteroaryl, heterocyclyl, —C(O)OR³, —C(O)NR³R⁴, —C(O)NR⁴OR³,—C(O)R⁴OR³, —C(O)NR⁴SO₂R³, —C(O)(C₃-C₁₀ cycloalkyl), —C(O)(C₁-C₁₀alkyl), —C(O)(aryl), —C(O)(heteroaryl), —C(O)(heterocyclyl) or CR³OR³,wherein any of said heteroaryl, heterocyclyl, —C(O)OR³, —C(O)NR³R⁴,—C(O)NR⁴OR³, —C(O)R⁴OR³, —C(O)NR⁴SO₂R³, —C(O)(C₃-C₁₀ cycloalkyl),—C(O)(C₁-C₁₀ alkyl), —C(O)(aryl), —C(O)(heteroaryl), —C(O)(heterocyclyl)and CR³OR³ are optionally substituted with one or more groupsindependently selected from halogen, cyano, nitro, azido, —NR³R⁴, —OR³,C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, cycloalkyl andheterocycloalkyl, wherein any of said C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl,C₂-C₁₀ alkynyl, cycloalkyl and heterocycloalkyl are optionallysubstituted with 1 or more groups independently selected from —NR³R⁴ and—OR;

provided that when X is CH, W cannot be C(O)aryl or C(O)heteroaryl;

further provided that when X is CH, W is C(O)OR³ and R⁹ is F, R⁷ cannotbe H;

m is 0, 1, 2, 3, 4 or 5; and

j is 0, 1 or 2.

FIGS. 15-34 show non-limiting examples of the synthesis of compounds ofthis invention having the general Formula V.

The terms “C₁-C₁₀ alkyl”, “alkyl” and “lower alkyl” as used herein referto a saturated linear or branched-chain monovalent hydrocarbon radicalhaving one to ten carbon atoms, wherein the alkyl radical may beoptionally substituted independently with one or more substituentsdescribed below. Examples of alkyl groups include, but are not limitedto, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, 2-hexyl,3-hexyl, 3-methylpentyl, heptyl, octyl, and the like.

The terms “C₂-C₁₀ alkenyl”, “lower alkenyl” and “alkenyl” refer tolinear or branched-chain monovalent hydrocarbon radical having two to 10carbon atoms and at least one double bond, and include, but is notlimited to, ethenyl, propenyl, 1-but-3-enyl, 1-pent-3-enyl, 1-hex-5-enyland the like, wherein the alkenyl radical may be optionally substitutedindependently with one or more substituents described herein, andincludes radicals having “cis” and “trans” orientations, oralternatively, “E” and “Z” orientations.

The terms “C₂-C₁₀ alkynyl,” “lower alkynyl” and “alkynyl” refer to alinear or branched monovalent hydrocarbon radical of two to twelvecarbon atoms containing at least one triple bond. Examples include, butare not limited to, ethynyl, propynyl, butynyl, pentyn-2-yl and thelike, wherein the alkynyl radical may be optionally substitutedindependently with one or more substituents described herein.

The term “allyl” refers to a radical having the formula RC═CHCHR,wherein R is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,aryl, heteroaryl, or any substituent as defined herein, wherein theallyl may be optionally substituted independently with one or moresubstituents described herein.

The terms “carbocycle,” “carbocyclyl,” “cycloalkyl” or “C₃-C₁₀cycloalkyl” refer to saturated or partially unsaturated cyclichydrocarbon radical having from three to ten carbon atoms. The term“cycloalkyl” includes monocyclic and polycyclic (e.g., bicyclic andtricyclic) cycloalkyl structures, wherein the polycyclic structuresoptionally include a saturated or partially unsaturated cycloalkyl fusedto a saturated or partially unsaturated cycloalkyl or heterocycloalkylring or an aryl or heteroaryl ring. Examples of cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and the like. The cycloalkyl may be optionallysubstituted independently in one or more substitutable positions withvarious groups. For example, such cycloalkyl groups may be optionallysubstituted with, for example, C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen,hydroxy, cyano, nitro, amino, mono(C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, amino(C₁-C₆)alkyl, mono(C₁-C₆)alkylamino(C₁-C₆)alkyl ordi(C₁-C₆)alkylamino(C₁-C₆)alkyl.

The term “heteroalkyl” refers to saturated linear or branched-chainmonovalent hydrocarbon radical of one to twelve carbon atoms, wherein atleast one of the carbon atoms is replaced with a heteroatom selectedfrom N, O, or S, and wherein the radical may be a carbon radical orheteroatom radical (i.e., the heteroatom may appear in the middle or atthe end of the radical). The heteroalkyl radical may be optionallysubstituted independently with one or more substituents describedherein. The term “heteroalkyl” encompasses alkoxy and heteroalkoxyradicals.

The terms “heterocycloalkyl,” “heterocycle” or “heterocyclyl” refer to asaturated or partially unsaturated carbocyclic radical of 3 to 8 ringatoms in which at least one ring atom is a heteroatom selected fromnitrogen, oxygen and sulfur, the remaining ring atoms being C, where oneor more ring atoms may be optionally substituted independently with oneor more substituent described below. The radical may be a carbon radicalor heteroatom radical. The term further includes fused ring systemswhich include a heterocycle fused to one or more aromatic groups.“Heterocycloalkyl” also includes radicals where heterocycle radicals arefused with one or more carbocyclic and/or heterocyclic rings. Examplesof heterocycloalkyl rings include, but are not limited to, pyrrolidinyl,tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino,thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl,oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl,diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl,3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl,dihydrothienyl, dihydrofuranyl, pyrazolidinylimidazolinyl,imidazolidinyl, 3-azabicyco[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl,azabicyclo[2.2.2]hexanyl, 3H-indolyl and quinolizinyl. Spiro moietiesare also included within the scope of this definition. The foregoinggroups, as derived from the groups listed above, may be C-attached orN-attached where such is possible. For instance, a group derived frompyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).Further, a group derived from imidazole may be imidazol-1-yl(N-attached) or imidazol-3-yl (C-attached). An example of a heterocyclicgroup wherein 2 ring carbon atoms are substituted with oxo (═O) moietiesis 1,1-dioxo-thiomorpholinyl. The heterocycle groups herein areunsubstituted or, as specified, substituted in one or more substitutablepositions with various groups. For example, such heterocycle groups maybe optionally substituted with, for example, C₁-C₆ alkyl, C₁-C₆ alkoxy,halogen, hydroxy, cyano, nitro, amino, mono(C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, amino(C₁-C₆)alkyl, mono(C₁-C₆)alkylamino(C₁-C₆)alkyl ordi(C₁-C₆)alkylamino(C₁-C₆)alkyl.

The term “aryl” refers to a monovalent aromatic carbocyclic radicalhaving a single ring (e.g., phenyl), multiple rings (e.g., biphenyl), ormultiple condensed rings in which at least one is aromatic, (e.g.,1,2,3,4-tetrahydronaphthyl, naphthyl), which is optionally mono-, di-,or trisubstituted with, e.g., halogen, lower alkyl, lower alkoxy,trifluoromethyl, aryl, heteroaryl, and hydroxy.

The term “heteroaryl” refers to a monovalent aromatic radical of 5-, 6-,or 7-membered rings which includes fused ring systems (at least one ofwhich is aromatic) of 5-10 atoms containing at least one and up to fourheteroatoms selected from nitrogen, oxygen, or sulfur. Examples ofheteroaryl groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl,triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl,benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl,phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl,oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl,benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl,quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. Spiromoieties are also included within the scope of this definition.Heteroaryl groups are optionally mono-, di-, or trisubstituted with,e.g., halogen, lower alkyl, lower alkoxy, haloalkyl, aryl, heteroaryl,and hydroxy.

The term “halogen” represents fluorine, bromine, chlorine, and iodine.

The term “arylalkyl” means an alkyl moiety (as defined above)substituted with one or more aryl moiety (also as defined above). Morepreferred arylalkyl radicals are aryl-C₁₋₃-alkyls. Examples includebenzyl, phenylethyl, and the like.

The term “heteroarylalkyl” means an alkyl moiety (as defined above)substituted with a heteroaryl moiety (also as defined above). Morepreferred heteroarylalkyl radicals are 5- or 6-memberedheteroaryl-C₁₋₃-alkyls. Examples include, oxazolylmethyl, pyridylethyland the like.

The term “heterocyclylalkyl” means an alkyl moiety (as defined above)substituted with a heterocyclyl moiety (also defined above). Morepreferred heterocyclylalkyl radicals are 5- or 6-memberedheterocyclyl-C₁₋₃-alkyls. Examples include tetrahydropyranylmethyl.

The term “cycloalkylalkyl” means an alkyl moiety (as defined above)substituted with a cycloalkyl moiety (also defined above). Morepreferred heterocyclyl radicals are 5- or 6-memberedcycloalkyl-C₁₋₃-alkyls. Examples include cyclopropylmethyl.

The term “Me” means methyl, “Et” means ethyl, “Bu” means butyl and “Ac”means acetyl.

The term “amino acid residue” includes, but is not limited to, the 20naturally occurring amino acids commonly designated by three lettersymbols, and also includes 4-hydroxyproline, hydroxylysine, demosine,isodemosine, 3-methylhistidine, norvaline, beta-alanine,gamma-aminobutyric acid, cirtulline, homocysteine, homoserine, ornithineand methionine sulfone.

In general, the various moieties or functional groups of the compoundsof Formulas I-V may be optionally substituted by one or moresubstituents. Examples of substituents suitable for purposes of thisinvention include, but are not limited to, oxo (with the proviso that itis not on an aryl or heteroaryl), halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR⁴SO₂R⁶,—SO₂NR³R⁴, —C(O)R³, —C(O)OR³, —OC(O)R³, —NR⁴C(O)OR⁶, —NR⁴C(O)R³,—C(O)NR³R⁴, —NR³R⁴, —NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —OR³, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl, where R³, R⁴, R⁵ and R⁶ are as defined herein.

It is to be understood that in instances where two or more radicals areused in succession to define a substituent attached to a structure, thefirst named radical is considered to be terminal and the last namedradical is considered to be attached to the structure in question. Thus,for example, the radical arylalkyl is attached to the structure inquestion by the alkyl group.

In the compounds of the present invention, where a term such as(CR⁴R⁵)_(m) is used, R⁴ and R⁵ may vary with each iteration of mabove 1. For instance, where m is 2, the term (CR⁴R⁵)_(m) may equal—CH₂CH₂— or —CH(CH₃)C(CH₂CH₃)(CH₂CH₂CH₃)— or any number of similarmoieties falling within the scope of the definitions of R⁴ and R⁵.

The compounds of this invention may possess one or more asymmetriccenters; such compounds can therefore be produced as individual (R)- or(S)-stereoisomers or as mixtures thereof. Unless indicated otherwise,the description or naming of a particular compound in the specificationand claims is intended to include both individual enantiomers,diastereomers mixtures, racemic or otherwise, thereof. Accordingly, thisinvention also includes all such isomers, including diastereomericmixtures and resolved enantiomers of the Formulas I-V. Diastereomericmixtures can be separated into their individual diastereomers on thebasis of their physical chemical differences by methods known to thoseskilled in the art, for example, by chromatography or fractionalcrystallization. Enantiomers can be separated by converting theenantiomer mixture into a diastereomeric mixture by reaction with anappropriate optically active compound (e.g., alcohol), separating thediastereomers and converting (e.g., hydrolyzing) the individualdiastereomers to the corresponding pure enantiomers. The methods for thedetermination of stereochemistry and the separation of stereoisomers arewell known in the art (see discussion in Chapter 4 of “Advanced OrganicChemistry”, 4th edition, J. March, John Wiley and Sons, New York, 1992).

This invention also encompasses pharmaceutical compositions containing acompound of Formula I-V and methods of treating proliferative disorders,or abnormal cell growth, by administering compounds of the presentinvention. Compounds of the present invention having free amino, amido,hydroxy or carboxylic groups can be converted into pharmaceuticallyacceptable prodrugs.

A “pharmaceutically acceptable prodrug” is a compound that may beconverted under physiological conditions or by solvolysis to thespecified compound or to a pharmaceutically acceptable salt of suchcompound. Prodrugs include compounds wherein an amino acid residue, or apolypeptide chain of two or more (e.g., two, three or four) amino acidresidues is covalently joined through an amide or ester bond to a freeamino, hydroxy or carboxylic acid group of compounds of the presentinvention. The amino acid residues include but are not limited to the 20naturally occurring amino acids commonly designated by three lettersymbols and also includes 4-hydroxyproline, hydroxylysine, demosine,isodemosine, 3-methylhistidine, norvaline, beta-alanine,gamma-aminobutyric acid, cirtulline, homocysteine, homoserine, ornithineand methionine sulfone. One preferred prodrug of this invention is acompound of Formula I-V covalently joined to a valine residue.

Additional types of prodrugs are also encompassed. For instance, freecarboxyl groups can be derivatized as amides or alkyl esters. As anotherexample, compounds of this invention comprising free hydroxy groups maybe derivatized as prodrugs by converting the hydroxy group to aphosphate ester, hemisuccinates dimethylaminoacetate, orphosphoryloxymethyloxycarbonyl, as outlined in Advanced Drug DeliveryReviews, 1996, 19, 115. Carbamate prodrugs of hydroxy and amino groupsare also included, as are carbonate prodrugs, sulfonate esters andsulfate esters of hydroxy groups. Derivatization of hydroxy groups as(acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may bean alkyl ester, optionally substituted with groups including but notlimited to ether, amine and carboxylic acid functionalities, or wherethe acyl group is an amino acid ester as described above, are alsoencompassed. Prodrugs of this type are described in J. Med. Chem., 1996,39, 10. More specific examples include replacement of the hydrogen atomof the alcohol group with a group such as (C₁-C₆)alkanoyloxymethyl,1-((C₁-C₆)alkanoyloxy)ethyl, 1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl,(C₁-C₆)alkoxycarbonyloxymethyl, N—(C₁-C₆)alkoxycarbonyl-aminomethyl,succinoyl, (C₁-C₆)alkanoyl, α-amino(C₁-C₄)alkanoyl, arylacyl andα-aminoacyl, or α-aminoacyl-α-aminoacyl, where each α-aminoacyl group isindependently selected from the naturally occurring L-amino acids,P(O)(OH)₂, —P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting fromthe removal of a hydroxyl group of the hemiacetal form of acarbohydrate).

Free amines can also be derivatized as amides, sulfonamides orphosphonamides. For example, a prodrug can be formed by the replacementof a hydrogen atom in the amine group with a group such as R-carbonyl,RO-carbonyl, NRR′-carbonyl where R and R′ are each independently(C₁-C₁₀)alkyl, (C₃-C₇)cycloalkyl, benzyl, or R-carbonyl is a naturalα-aminoacyl or natural .alpha.-aminoacyl-natural α-aminoacyl,—C(OH)C(O)OY wherein Y is H, (C₁-C₆)alkyl or benzyl, —C(OY₀)Y₁ whereinY₀ is (C₁-C₄) alkyl and Y₁ is (C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl,amino(C₁-C₄)alkyl or mono-N- or di-N,N—(C₁-C₆)alkylaminoalkyl, —C(Y₂)Y₃wherein Y₂ is H or methyl and Y₃ is mono-N- or di-N,N—(C₁-C₆)alkylamino,morpholino, piperidin-1-yl or pyrrolidin-1-yl.

All of these prodrug moieties may incorporate groups including but notlimited to ether, amine and carboxylic acid functionalities.

In addition, the invention also includes solvates, pharmaceuticallyactive metabolites, and pharmaceutically acceptable salts of compoundsof Formulas I-V.

The term “solvate” refers to an aggregate of a molecule with one or moresolvent molecules.

A “pharmaceutically active metabolite” is a pharmacologically activeproduct produced through metabolism in the body of a specified compoundor salt thereof. Metabolites of a compound may be identified usingroutine techniques known in the art and their activities determinedusing tests such as those described herein.

Prodrugs and active metabolites of a compound may be identified usingroutine techniques known in the art. Various forms of prodrugs are knownin the art. For examples of such prodrug derivatives, see, for example,a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) andMethods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al.(Academic Press, 1985); b) A Textbook of Drug Design and Development,edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design andApplication of Prodrugs,” by H. Bundgaard p. 113-191 (1991); c) H.Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); d) H.Bundgaard, et al., Journal of Pharmaceutical Sciences, 77:285 (1988);and e) N. Kakeya, et al., Chem. Pharm. Bull., 32: 692 (1984), each ofwhich is specifically incorporated herein by reference.

A “pharmaceutically acceptable salt” as used herein, unless otherwiseindicated, includes salts that retain the biological effectiveness ofthe free acids and bases of the specified compound and that are notbiologically or otherwise undesirable. A compound of the invention maypossess a sufficiently acidic, a sufficiently basic, or both functionalgroups, and accordingly react with any of a number of inorganic ororganic bases, and inorganic and organic acids, to form apharmaceutically acceptable sale. Examples of pharmaceuticallyacceptable salts include those salts prepared by reaction of thecompounds of the present invention with a mineral or organic acid or aninorganic base, such salts including sulfates, pyrosulfates, bisulfates,sulfites, bisulfites, phosphates, monohydrogenphosphates,dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides,bromides, iodides, acetates, propionates, decanoates, caprylates,acrylates, formates, isobutyrates, caproates, heptanoates, propiolates,oxalates, malonates, succinates, suberates, sebacates, fumarates,maleates, butyn-1,4-dioates, hexyne-1,6-dioates, benzoates,chlorobenzoates, methylbenzoates, dinitromenzoates, hydroxybenzoates,methoxybenzoates, phthalates, sulfonates, xylenesulfonates,pheylacetates, phenylpropionates, phenylbutyrates, citrates, lactates,γ-hydroxybutyrates, glycollates, tartrates, methanesulfonates,propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates,and mandelates. Since a single compound of the present invention mayinclude more than one acidic or basic moieties, the compounds of thepresent invention may include mono, di or tri-salts in a singlecompound.

If the inventive compound is a base, the desired pharmaceuticallyacceptable salt may be prepared by any suitable method available in theart, for example, treatment of the free base with an acidic compound,particularly an inorganic acid, such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid and the like, or withan organic acid, such as acetic acid, maleic acid, succinic acid,mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid,glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronicacid or galacturonic acid, an alphahydroxy acid, such as citric acid ortartaric acid, an amino acid, such as aspartic acid or glutamic acid, anaromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid,such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.

If the inventive compound is an acid, the desired pharmaceuticallyacceptable salt may be prepared by any suitable method, for example,treatment of the free acid with an inorganic or organic base. Preferredinorganic salts are those formed with alkali and alkaline earth metalssuch as lithium, sodium, potassium, barium and calcium. Preferredorganic base salts include, for example, ammonium, dibenzylammonium,benzylammonium, 2-hydroxyethylammonium, bis(2-hydroxyethyl)ammonium,phenylethylbenzylamine, dibenzyl-ethylenediamine, and the like salts.Other salts of acidic moieties may include, for example, those saltsformed with procaine, quinine and N-methylglusoamine, plus salts formedwith basic amino acids such as glycine, ornithine, histidine,phenylglycine, lysine and arginine.

Processes for the manufacture of the compounds of Formula I, Formula II,Formula III, Formula IV and Formula V are provided as further featuresof the invention. The inventive compounds may be prepared using thereaction routes and synthesis schemes as described below, employing thetechniques available in the art using starting materials that arereadily available or can be synthesized using methods known in the art.

Illustrations of the preparation of compounds of the present inventionare shown in FIGS. 1-34.

FIG. 1 illustrates synthesis of compounds of Formula I. Pyridone ester 2can be prepared in a two step one-pot procedure. Treatment of3-oxo-pentanedioic acid diethyl ester 1 with triethyl orthoformate andacetic acid at elevated temperatures (120 to 150° C.) gives theintermediate enol ether. Cyclization of the enol ether intermediate canthen be accomplished by cooling the concentrated reaction residue andtreating with the appropriate amine at low temperature (about 0° C.).Halogenation of the pyridone ester 2 can be accomplished with POCl₃,thionyl chloride, oxalyl chloride, PCl₅, PBr₃, or Ph₃P and Br₂.Preferably this transformation is achieved with POCl₃ neat or in thepresence of an amine like triethylamine at room temperature. If R⁹ is Clor F, it can be incorporated at this stage. Chlorination of pyridoneester 3 can be accomplished with NCS in a suitable organic solvent suchas DMF, MeCN or mixed solvent systems at room temperature. Preferablythe reaction is carried out in DMF. Fluorination is achieved by treatingpyridone ester 3 with[1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane-bis(tetrafluoroborate)in the presence of base in a suitable organic solvent at the appropriatetemperature. Most preferable is the use of LiOH as base and MeCN assolvent at approximately 85° C.

With continued reference to FIG. 1, regardless of the identity of R⁹,pyridone acid 4 can be prepared by basic hydrolysis under standardconditions using either LiOH or NaOH in standard mixed aqueous/organicsolvent systems. Incorporation of the aniline moiety is accomplished byS_(N)Ar reaction. This can be done in a suitable organic solvent such asTHF using an amide base such as LDA, LiHMDS, NaHMDS or KHMDS atappropriate temperatures (−78° C. to room temperature). Preferably, theaniline is added to LDA or LiHMDS in THF at low temperature (−20 to −80°C.). The pyridone 4 is then added and the reaction mixture is warmed toroom temperature to generate carboxylic acid 5 . Amides 6 andhydroxamates 7 can be prepared using standard coupling procedures,including but not limited to EDCI, HOBt, or PyBOP and the appropriateamine or hydroxylamine in suitable organic solvents such as DMF, THF ormethylene chloride. In some instances, the amine or hydroxylamine usedin the coupling reaction contains a standard protecting group. In thosecases, the protecting group can be removed by standard conditions knownin the art.

FIG. 2 outlines the synthesis of compounds of Formula I wherein the R⁹group is incorporated into the starting 3-oxopentanedioic acid diethylester 8. This route is particularly useful for analogs where R⁹ isalkyl. The preparation of analog 10 is outlined in FIG. 2 and can becarried out as described above for FIG. 1 with the addition thatactivation of pyridone 9 can be accomplished by conversion to a triflateester. This can be done by treating pyridone 9 with triflic anhydride orN-phenyltrifluoromethanesulfonimide and amine base in THF or methylenechloride. When Z is Cl or Br, pyridone 10 can be converted to amide 6 orhydroxmate 7 as described in FIG. 1. Alternatively, pyridone 10 can beconverted to hydroxamate 7 in the route outlined in FIG. 2 in which theaniline moiety is incorporated utilizing palladium mediated crosscoupling chemistry. The palladium mediated cross coupling chemistry canbe accomplished by treatment of a mixture of the appropriate aniline andpyridone 10 with a Pd catalyst such as Pd(OAc)₂, PdCl₂(dppf), Pd(Ph₃P)₄,Pd₂ dba₃, a phosphine ligand and base in a suitable organic solvent suchas THF, DMF, PhMe, DME or MeCN at elevated temperature. Most preferably,Pd(OAc)₂, rac-2,2-bis(diphenylphosphino)-1,1′-binaphthyl and Cs₂CO₃ areused in PhMe at 70 to 100° C. Hydroxamate 7 can be prepared by treatingpyridone ester 11 with the appropriate hydroxylamine and amide base suchas LDA, LiHMDS or NaHMDS in a suitable organic solvent such as THF atlow temperature. Preferably, a LiHMDS solution is added to a solution ofpyridone ester 11 and hydroxylamine in THF at 0° C. The reaction mixtureis then warmed to room temperature to yield the desired hydroxamate 7.In some instances, the hydroxylamine used in the coupling reactioncontains a standard protecting group. In those cases, the protectinggroup can be removed by standard conditions known in the art.

In FIG. 3 preparation of compounds of the Formula I is shown in which4,6-dichloro-5-fluoronicotinic acid 12 (Sanchez et al J Heterocylc.Chem. 1993, 30 (4), 855-9) is used as the starting material. Ester 13can be prepared in a two-step procedure. The first step is SNAr additionof the properly substituted aniline in a suitable organic solvent suchas THF using an amide base such as LDA, LiHMDS, NaHMDS or KHMDS atappropriate temperatures (−78° C. to room temperature). Preferably, theaniline is added to LDA or LiHMDS in THF at low temperature (−20 to −80°C.). The nicotinic acid 12 is then added and the reaction mixture warmedto room temperature to generate the corresponding carboxylic acid. Themethyl ester 13 can then be prepared by standard conditions includingbut not limited to TMSCl in MeOH or TMSCHN₂ in suitable organic solventssuch as PhMe/MeOH. Pyridone 14 can be made in a two-step sequence. Inthe first step, methyl ester 13 is treated with sodium methoxide in asuitable organic solvent such as MeOH or THF or MeOH/THF mixtures attemperatures ranging from 0° C. to 40° C. Preferably, sodium methoxideis added to a solution of methyl ester 13 in MeOH/THF at 0° C. Thismixture is then warmed to room temperature and then to 40° C. togenerate the desired methoxy pyridine. Demethylation can then beaccomplished by standard conditions including but not limited to aqueousHCl at elevated temperature, pTsOH in acetic acid at elevatedtemperature and aqueous HBr in MeOH at elevated temperature. Preferablydemethylation to give pyridone 14 is achieved by treatment of themethoxy pyridine with HBr in acetic acid at elevated temperature (80 to120° C.). If desired, alkylation of pyridone 14 to give substitutedpyridone 15 can be achieved by standard basic alkylation conditionsincorporating alkyl halides. These conditions include but are notlimited to K₂CO₃ in acetone or DMF, NaH in THF or, NaOMe in MeOH/PhMeor, phase transfer conditions using for example NaOH and Bu₄NI.Preferably, the alkylation is accomplished by treatment of pyridone 14with LiH at 0° C. in DMF followed by addition of alkyl bromide andwarming to room temperature. Carboxylic acid 15 can then be preparedusing standard saponification conditions such as LiOH or NaOH instandard mixed aqueous/organic solvent systems. Pyridone 15 can beconverted to amide 6 or hydroxmate 7 as described in FIG. 1.

FIG. 4 describes the initial steps in the preparation of analogs ofcompounds of the Formula I. Treatment of 3-oxopentanedioic acid diethylester 8 with a ketene acetal and acetic acid at elevated temperatures(120 to 150° C.) gives the intermediate enol ether. Cyclization of theenol ether intermediate can then be accomplished by cooling theconcentrated reaction residue and treating with the appropriate amine atlow temperature (about 0° C.) to give pyridone 16. If R⁹ is Cl or F isdesired, then a chlorination or fluorination step as described in FIG. 1can be incorporated at this time. Furthermore, pyridone 16 can beconverted to amide 6 or hydroxamate 7 through the SNAr chemistry asdescribed in FIG. 1 or through palladium mediated cross-couplingchemistry as described in FIG. 2.

In FIG. 5 syntheses of compounds of Formula II and IV are depicted.Bromination of pyridone 17 (prepared as described in FIGS. 2 and 4) togive pyridone 18 can be accomplished using standard conditions such asNBS in a suitable organic solvent. Cyclization to form lactam 19 can beachieved by treatment with ammonia or a primary amine in a suitableorganic solvent at temperatures ranging from ambient to slightlyelevated. Preferably, this cyclization is accomplished in an alcoholicsolvent such as MeOH or EtOH. Pyridone 18 can also be converted topyridazinones 20 and 21 by treatment with substituted or unsubstitutedhydrazines or t-butyl carbazate in a suitable organic solvent such asDMF, THF, MeOH or EtOH. Pyridazinones 20 and 21 can then be substitutedfurther by standard basic alkylation conditions with alkyl halides.These conditions include but are not limited to K₂CO₃ in acetone or DMFat room or elevated temperature, NaH in THF or DMF at ambient orelevated temperature, and NaOMe in MeOH/PhMe at elevated temperature.Pyridazinone 21 can be then be deprotected under standard conditionsincluding, but not limited to, TFA in methylene chloride or HCl in asuitable organic solvent such as dioxane.

FIG. 6 depicts the preparation of compounds of the Formula I where X isN. In FIG. 6,4-hydroxy-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxylic acid methylester 24 (Schober et al J. Heterocyclc. Chem. 1989, 26, 169-176) can beconverted to dihydropyridazine 25 in one of two procedures. The firstmethod involves halogenation followed by SNAr reaction and in situsaponification. Halogenation of the pyridazine ester 24 can beaccomplished with POCl₃, thionyl chloride, oxalyl chloride, PCl₅, PBr₃,or Ph₃P and Br₂. Preferably this transformation is achieved with POCl₃neat at elevated temperature (about 85° C.). If R⁹ is Cl or F isdesired, then chlorination or fluorination as described in FIG. 1 can beincorporated at this time. In the second step, aniline addition andsaponification can be carried out in the same pot. The SNAr reaction canbe done in a suitable organic solvent such as 1,2-dichlorobenzene,xylenes, or toluene in the presence of a base such as Cs₂CO₃ or K₂CO₃ atelevated temperature (80 to 200° C.). Preferably the SNAr reaction isaccomplished by treating the halogenated pyridazine with aniline andCs₂CO₃ in 1,2-dichlorobenzene and heating to 180° C. for 24 hours.Saponification to generate dihydropyridazine 25 is accomplished by theaddition of water to the crude reaction mixture stirring at roomtemperature. The second method involves halogenation or activation ofpyridazine ester 24 followed by palladium mediated cross-coupling.Halogenation is accomplished as described above. Activation can be doneby treating pyridazine ester 24 with triflic anhydride orN-phenyltrifluoromethanesulfonimide and amine base in THF or methylenechloride. In the case where halogenation is used, if R⁹ is Cl or F isdesired, then a chlorination or fluorination step as described in FIG. 1can be incorporated at this time. The palladium mediated cross-couplingreaction can be achieved by standard methods including but not limitedto treating the halogenated or activated pyridazine with aniline, Pdcatalyst such as Pd(OAc)₂, PdCl₂(dppf), Pd(Ph₃P)₄, Pd₂ dba₃, a phosphineligand and base in a suitable organic solvent such as THF, DMF, PhMe,DME or MeCN at elevated temperature. Saponification to generateddihydropyridazine 25 can be achieved as described above by the additionof water to the crude reaction mixture stirring at room temperature orby basic hydrolysis under standard conditions using either LiOH or NaOHin standard mixed aqueous/organic solvent systems. Dihydropyridazine 25can be converted to amide 26 or hydroxmate 27 by the standard methodsdescribed in FIG. 1 or FIG. 2.

The preparation of compounds of the Formula I where X═N is depicted inFIG. 7. Substituted hydrazine 28 can be converted to hydrazono-propionicacid ethyl ester 29 by a two-step procedure. In the first step,hydrazine 28 is condensed with ethyl pyruvate under standard dehydratingconditions such as in the presence of MgSO₄ in a suitable organicsolvent such as chloroform or methylene chloride at temperatures rangingfrom 0° C. to ambient temperature. In the second step, acylation isachieved by treatment with base at low temperature in a suitable organicsolvent such as THF, DMF, dioxane or MeCN followed by the addition ofmethyl malonyl chloride. Preferably, the hydrazone is treated with LiHin THF at 0° C. followed by the addition of methyl malonyl chloride andwarming to room temperature. 5-Hydroxy-2H-pyridazin-3-one 31 is preparedfrom hydrazono-propionic acid ethyl ester 29 by cyclization understrongly basic conditions followed by saponification anddecarboxylation. The cyclization can be accomplished by treatment ofhydrazono-propionic acid ethyl ester 29 with a strong base such as DBU,LDA or NaH in a suitable organic solvent such as THF or MeCN at roomtemperature. Preferably, cyclization is achieved with DBU in MeCN atroom temperature. Decarboxylation to form 5-hydroxy-2H-pyridazin-3-one31 can be achieved by heating5-hydroxy-3-oxo-2,3-dihydropyridazine-4-carboxylic acid methyl ester 30in a suitable organic solvent such as dioxane or decalin ordioxane/decalin mixture to high temperatures in the presence ofconcentrated HCl. 5-Chloro-2H-pyridazin-3-one 32 can be prepared from5-hydroxy-2H-pyridazin-3-one 31 by treatment with POCl₃, thionylchloride, oxalyl chloride or PCl₅. Preferably this transformation isachieved with POCl₃ neat at elevated temperature (˜85° C.). If R⁹ is Clor F is desired, then a chlorination or fluorination step as describedin FIG. 1 can be incorporated either after decarboxylation or afterchlorination. Carboxylic acid 33 can be prepared by oxidation understandard conditions including but not limited to KMnO₄ in water, SeO₂ inorganic solvent like dioxane, xylene, or pyridine, NaOCl/RuCl₃, CrO₃ inaqueous H₂SO₄, K₂Cr₂O₇, and Na₂Cr₂O₇ in water. Preferably thistransformation is achieved with K₂Cr₂O₇—H₂SO₄. Carboxylic acid 33 can beconverted to amide 26 or hydroxmate 27 by the standard methods such asthose described in FIGS. 1, 2 and 6.

FIG. 8 illustrates the preparation of compounds of Formula III. Pyridone11 can be converted to bromide 34 by standard conditions including butnot limited to NBS or bromine with or without a variety of additivessuch as AcOH, H₂O₂, silica, AlCl₃ and t-BuNH₂, in a suitable solventsuch as CCl₄ or water. Synthesis of ketone 35 can be accomplished in atwo-step procedure. In the first step, palladium mediated alkyne crosscoupling reaction is used to generate the corresponding alkyneintermediate. This palladium mediated cross-coupling reaction can beachieved by standard methods including but not limited to treatingbromide 34 with desired alkyne, Pd catalyst such as Pd(OAc)₂ and Ph₃P,PdCl₂(dppf), Pd(Ph₃P)₂Cl₂, Pd(Ph₃P)₄, Pd₂ dba₃ and Ph₃P, CuI, and aminebase such as Et₃N, Et₂NH, or iPr₂NH, in a suitable organic solvent suchas THF, DMF, PhMe, DME or MeCN at elevated temperature. More preferably,the bromide 34 and alkyne are treated with Pd(Ph₃P)₂Cl₂, CuI and aminebase in THF or DMF at 50 to 100° C. In the second step, the intermediatealkyne is hydrolysized to the ketone 35 by standard methods includingbut not limited to H₂SO₄, TFA, trifluorosulfonamide, FeCl₃ orHgSO₄/H₂SO₄. Cyclization to form pyrido-pyridazine-dione 36 can beaccomplished by treating ketone 35 with substituted or unsubstitutedhydrazine in a suitable organic solvent such as EtOH, iPrOH, DMF, DME ormixtures thereof at temperatures ranging from ambient to about 100° C.

Compounds of Formula III can be prepared as outlined in FIG. 9. Bromide37 can be synthesized from pyridone 9 by chlorination followed byaromatic bromination. The chlorination can be accomplished with POCl₃,thionyl chloride, oxalyl chloride, PCl₅, PBr₃, or Ph₃P and Br₂.Preferably this transformation is achieved with POCl₃ neat at elevatedtemperature (about 85° C.). If R⁹ is Cl or F, then a chlorination orfluorination step as described in FIG. 1 can be incorporated at thistime. Aromatic bromination can be achieved by standard conditionsincluding but not limited to NBS or bromine with or without a variety ofadditives such as AcOH, H₂O₂, silica, AlCl₃ and t-BuNH₂, in a suitablesolvent such as CCl₄ or water. Ketone 38 and pyrido-pyridazine-dione 39can be prepared as described in FIG. 8. Pyridopyridazine-dione 40 can bemade from pyridopyridazine-dione 39 by palladium mediated cross couplingchemistry. The palladium mediated cross-coupling reaction can beachieved by standard methods including but not limited to treatingpyridopyridazine-dione 39 with the appropriate aniline, Pd catalyst suchas Pd(OAc)₂, PdCl₂(dppf), Pd(Ph₃P)₄, Pd₂ dba₃, a phosphine ligand andbase in a suitable organic solvent such as THF, DMF, PhMe, DME or MeCNat elevated temperature.

FIGS. 10-12 illustrate the preparation of compounds of Formula I of thepresent invention where W is heterocyclic or heteroaromatic. Hydrazide42 can be prepared from carboxylic acid 41 by standard couplingprocedures including but not limited to EDCI, HOBt, or PyBOP andhydrazine in suitable organic solvents such as DMF, THF ordichloromethane. Amino oxadiazole 43 is prepared from hydrazide 42 bytreatment with BrCN and a base such as NaHCO₃, in a suitable biphasicsolvent system such as dioxane and water at room temperature.Oxadiazolone 44 can be prepared from hydrazide 42 using either CDI,phosgene or a phosgene equivalent in a suitable organic solvent such asDMF, PhMe, methylene chloride or mixtures thereof. Preferably,cyclization to form oxadiazolone 44 is accomplished by treatinghydrazide 42 with CDI in DMF at room temperature. Amino triazole 45 canbe prepared by treatment of the hydrazide 42 with cyanamide, followed bycyclization using PPh₃, TEA, and CCl₄ in dichloromethane. Similarly,triazole 46 can be prepared by treatment of the hydrazide 42 with ethylacetimidate, followed by cyclization using PPh₃, TEA, and CCl₄ indichloromethane. Substituted amino oxadiazole 47 can be prepared in atwo-step procedure from oxadiazolone 44 as outlined in FIG. 11.Oxadiazolone 44 is treated with a primary or secondary amine at elevatedtemperature in alcoholic solvents such as MeOH, EtOH or iPrOH.Preferably, a primary or secondary amine is stirred with oxadiazolone 44in EtOH at approximately 90° C. The ring-opened intermediate is thencyclized by treatment with PPh₃, TEA, and CCl₄ in dichloromethane togive substituted amino oxadiazole 47. In some cases the primary orsecondary amine used in the addition step contains a functionality thatrequires protection with a standard protecting group. In these cases,the protecting group can be removed under standard conditions to yieldthe desired substituted amino oxadiazole 47. The thiazole 48 can beprepared from the carboxylic acid 41 with thiosemicarbazide usingstandard EDCI coupling conditions followed by cyclization of theintermediate obtained employing PPh₃, TEA, and CCl₄ in dichloromethaneas outlined in FIG. 12.

FIG. 13 illustrates the preparation of compounds of Formula I. Acylsulfonamide 49 can be prepared from carboxylic acid 41 using standardcoupling procedures including but not limited to CDI or EDCI, HOBt, orPyBOP and the appropriate sulfonamide in suitable organic solvents suchas DMF, THF or dichloromethane in the presence of base. Preferably,carboxylic acid 41 is treated with CDI in DMF at room temperaturefollowed, a few hours later, by the addition of the appropriatesulfonamide and DBU.

FIG. 14 illustrates the synthesis of compounds of Formula I where W is aketone. Ketone 51 can be prepared either by treating methyl ester 50with Tebbe's reagent followed by aqueous acid or in a four-stepoxidative reduction protocol which utilizes alkyllithium or Grignardreagent addition to the corresponding aldehyde. The four-step protocolcan be accomplished as follows. The methyl ester 50 is reduced withNaBH₄ in EtOH at room temperature followed by oxidation with MnO₂ inTHF:acetone at 50° C. to give the corresponding aldehyde. The secondaryalcohol is then prepared by addition of either a Grignard reagent or analkyllithium to the aldehyde at −78° C. The ketone 51 is then preparedby MnO₂ oxidation of the corresponding secondary alcohol in THF:acetoneat 50° C.

In FIG. 15, synthesis of compounds of Formula V where X is CH and R⁹ isH or F is depicted, in which 2,6-dichloronicotinic acid or2,6-dichloro-5-fluoronicotinic acid is used as the starting material.The nicotinic acid 52 is converted to the monochloro acid 53 byrefluxing in 2N aqueous NaOH following the procedure described in U.S.Pat. No. 3,682,932. Alkylation of 53 can be achieved by standard basicalkylation conditions incorporating alkyl halides, with two equivalentsof the appropriate alkyl halide and base to give a mixture of theN-alkyl pyridone ester and the regioisomeric O-alkyl pyridine ester,which are easily separated by column chromatography. These conditionsinclude but are not limited to K₂CO₃ in acetone or DMF at room orelevated temperature or NaH in THF at ambient or elevated temperatureand then addition of the alkyl halide. Preferably this alkylation isachieved with LiH in DMF at 0° C., followed by addition of alkyl bromideor alkyl iodide and warming to room temperature. Incorporation of theproperly substituted aniline moiety is accomplished by S_(N)AR reaction.This can be done in a suitable organic solvent such as THF using anamide base such as LDA, LiHMDS, NaHMDS, or KHMDS at appropriatetemperatures (−78° C. to room temperature. Preferably the aniline isadded to LDA or LiHMDS in THF at low temperature (−20 to −80° C.). Thepyridone is then added and the mixture is stirred at low temperature togenerate ester 54. Carboxylic acid 55 can then be prepared usingstandard saponification conditions such as LiOH or NaOH in standardmixed aqueous/organic solvent systems. Hydroxamate 56 and amide 57 canbe prepared using standard coupling procedures, including but notlimited to EDCI, HOBt, or PyBOP and the appropriate amine orhydroxylamine in suitable organic solvents such as DMF, THF, ormethylene chloride. Preferably, the coupling is accomplished with HOBtand EDCI in DMF. In some instances, the amine or hydroxylamine used inthe coupling reaction contains a standard protecting group. In thosecases, the protecting group can be removed by standard conditions knownin the art.

In FIG. 16, an alternative synthesis of compounds of Formula V where Xis CH and R⁹ is H or F is depicted, in which 2,6-dichloronicotinic acidor 2,6-dichloro-5-fluoronicotinic acid is used as the starting material.This route is particularly useful for analogs where R⁷ is not Me or Et.Nicotinic acid 52 can be converted to the N-alkyl pyridone methyl ester54 following a five step procedure, where 2,6-dichloronicotinic acid 52is first converted to the methoxy pyridine acid, which is esterified togive the methyl ester and then deprotected to yield the monochloro ester58. The conversion to the methoxy pyridine acid is preferably carriedout by adding potassium t-butoxide to a solution of the acid 52 in MeOHand this mixture is then heated to reflux for several days.Esterification to give the methyl ester can be carried out understandard conditions, including but not limited to Fisher esterification(MeOH, H₂SO₄), TMSCl in MeOH or TMSCHN₂ in suitable organic solventssuch as PhMe/MeOH. Demethylation of the methoxy pyridine can then beaccomplished by standard conditions including but not limited to HCl atelevated temperature, pTsOH in acetic acid at elevated temperature andaqueous HBr in MeOH at elevated temperature. Preferable demethylation togive pyridone 58 is achieved by treatment of the methoxy pyridine withaqueous HBr in acetic acid at elevated temperature (80 to 120° C.).Alkylation of 58 can be achieved by standard basic alkylation conditionsincorporating alkyl halides, with one equivalent of the appropriatealkyl halide and base to give a mixture of the N-alkyl pyridone esterand the regioisomeric O-alkyl pyridine ester, which are easily separatedby column chromatography. These conditions include but are not limitedto K₂CO₃ in acetone or DMF at room or elevated temperature or NaH in THFat ambient or elevated temperature and then addition of the alkylhalide. Preferably this alkylation is achieved with LiH in DMF at 0° C.,followed by addition of alkyl bromide or alkyl iodide and warming toroom temperature. Incorporation of the properly substituted anilinemoiety is accomplished by S_(N)AR reaction. This can be done in asuitable organic solvent such as THF using an amide base such as LDA,LiHMDS, NaHMDS, or KHMDS at appropriate temperatures (−78° C. to roomtemperature. Preferably the aniline is added to LDA or LiHMDS in THF atlow temperature (−20 to −80° C.). The pyridone is then added and themixture is stirred at low temperature to generate ester 54. Hydroxamate56 can be prepared directly from methyl ester 54 in a suitable organicsolvent such as THF using the appropriate hydroxylamine and amide basesuch as LDA, LiHMDS, NaHMDS, or KHMDS at appropriate temperatures (−78°C. to room temperature). Preferably, a solution of LiHMDS is added to asolution of the methyl ester 54 and the hydroxylamine in THF at 0° C.The reaction mixture is then warmed to room temperature to yield thedesired hydroxamate 56. In some instances, the hydroxylamine used in thecoupling reaction contains a standard protecting group. In those cases,the protecting group can be removed by standard conditions known in theart.

In FIG. 17, another alternative synthesis of compounds of Formula Vwhere X is CH and R⁹ is H or F and R⁷ is H is depicted, in which2,6-dichloronicotinic acid or 2,6-dichloro-5-fluoronicotinic acid isused as the starting material. Formation of 59 can be accomplished byincorporation of the properly substituted aniline moiety into nicotinicacid 52 by S_(N)AR reaction. This can be done in a suitable organicsolvent such as THF using an amide base such as LDA, LiHMDS, NaHMDS, orKHMDS at appropriate temperatures (−78° C. to room temperature.Preferably the aniline is added to LDA or LiHMDS in THF at lowtemperature (−20 to −80° C.). Nicotinic acid 52 is then added and themixture is stirred at low temperature to generate the coupled product.Esterification to give the methyl ester can be carried out understandard conditions, including but not limited to Fisher esterification(MeOH, H₂SO₄), TMSCl in MeOH or TMSCHN₂ in suitable organic solventssuch as PhMe/MeOH. Pyridone 54 can be made in a two step sequence. Inthe first step, methyl ester 59 is treated with sodium methoxide in asuitable organic solvent such as MeOH or THF or MeOH/THF mixtures attemperatures ranging from 0° C. to reflux. Preferably, sodium methoxideis added to a solution of methyl ester 59 in MeOH at room temperature.This mixture is then refluxed for 4 days to generate the desired methoxypyridine. Demethylation of the methoxy pyridine can then be accomplishedby standard conditions including but not limited to HCl at elevatedtemperature, pTsOH in acetic acid at elevated temperature and aqueousHBr in MeOH at elevated temperature. Preferable demethylation to givepyridone 54 is achieved by treatment of the methoxy pyridine withaqueous HBr in acetic acid at elevated temperature (80 to 120° C.).Carboxylic acid 55, as well as hydroxamate 56 and amide 57 can then beprepared as described for FIG. 15.

In FIG. 18, the synthesis of compounds of Formula V where X is CH and R⁸is not H is depicted, in which 2,6-dichloronicotinic acid is used as thestarting material. Bromination of pyridone ester 54 can be accomplishedwith either Br₂ and acetic acid or NBS in a suitable organic solventsuch as DMF. Preferably NBS is added to a solution of pyridone ester 54in DMF to yield 60. Conversion of 60 to carboxylic acid 55, as well ashydroxamate 56 and amide 57 (where R⁹ is Br) can be accomplished asdescribed for FIGS. 15 and/or 16. Conversion of bromide 60 to compoundsof Formula V where R⁹ is aryl, heteroaryl, alkyl, cycloalkyl, alkenyl,alkynyl, amino and anilino can be achieved using Pd mediatedcross-coupling conditions, When R⁹ is alkenyl or alkynyl, these can befurther reduced using the appropriate reducing agent to provide alkylsubstituents at R⁹. In general, this chemistry can be accomplished usinga wide variety of Pd catalysts and ligands, with or without added base,in a suitable organic solvent such as DMF, PhMe, DME, THF, CH₃CN atelevated temperature. The coupling partner will depend on the nature ofR⁹. These Pd mediated cross-couplings are well documented in theliterature and are known by anyone skilled in the art. Conversion of 54to carboxylic acid 55, as well as hydroxamate 56 and amide 57 can beaccomplished as described for FIGS. 15 and/or 16.

In FIG. 19, the synthesis of compounds of Formula V is depicted, where Xis N. Pyrazinone ester 61, which can be synthesized as shown in FIG. 21or 22, can be converted to carboxylic acid 62, using standardsaponification conditions such as LiOH or NaOH in standard mixedaqueous/organic solvent systems. Hydroxamate 63 and amide 64 can beprepared using standard coupling procedures, including but not limitedto EDCI, HOBt, or PyBOP and the appropriate amine or hydroxylamine insuitable organic solvents such as DMF, THF, or methylene chloride. Insome instances, the amine or hydroxylamine used in the coupling reactioncontains a standard protecting group. In those cases, the protectinggroup can be removed by standard conditions known in the art.

In FIG. 20, the synthesis of compounds of Formula V is depicted, where Xis N. Pyrazinone ester 61, which can be synthesized as shown in FIG. 21or 22, can be directly converted to hydroxamate 63 in a suitable organicsolvent such as THF using the appropriate hydroxylamine and an amidebase such as LDA, LiHMDS, NaHMDS, or KHMDS at appropriate temperatures(−78° C. to room temperature). In some instances, the hydroxylamine usedin the coupling reaction contains a standard protecting group. In thosecases, the protecting group can be removed by standard conditions knownin the art.

In FIG. 21, the synthesis of pyrazinone ester 61, which is utilized asstarting material in FIGS. 19 and 20, is depicted. The aniline moiety isincorporated into aminopyrazinone 65 utilizing palladium mediatedcross-coupling chemistry. The palladium mediated cross couplingchemistry can be accomplished by treatment of a mixture of aniline andaminopyrazinone 65 with a Pd catalyst such as Pd(OAc)₂, PdCl₂(dppf),Pd(Ph₃P)₄, Pd₂ dba₃, a phosphine ligand and base in a suitable organicsolvent such as THF, DMF, PhMe, DME or MeCN at elevated temperature. IfR⁸ is Br or I, then a bromination or iodination step can be incorporatedafter the cross-coupling reaction. Thus, halogenation of 66 can beaccomplished with either NIS or NBS in a suitable organic solvent suchas DMF, MeCN or mixed solvent systems at room temperature to provide 61.

In FIG. 22, an alternative synthesis of pyrazinone ester 61, which isutilized as starting material in FIGS. 19 and 20, is depicted.Diazotization of 61 with nitrous acid in the presence of sulfuric acidyields the dizaonium salt, which can be further reacted with HBr andCuBr to yield bromide 67. Formation of 61 can then be accomplished byincorporation of the properly substituted aniline moiety into bromide 67by S_(N)AR reaction. This can be done in a suitable organic solvent suchas THF using an amide base such as LDA, LiHMDS, NaHMDS, or KHMDS atappropriate temperatures (−78° C. to room temperature. Preferably theaniline is added to LDA or LiHMDS in THF at low temperature (−20 to −80°C.). Bromide 67 is then added and the mixture is stirred at lowtemperature to generate the coupled product 61.

In FIGS. 23-27, several syntheses of aminopyrazinone 65, which is usedas the starting material in FIGS. 21 and 22, are depicted, depending onthe identity of R⁹. FIG. 23 depicts the synthesis of the aminopyrazinonecore where R⁹ is H. 3-Amino-5-oxo-4,5-dihydropyrazine-2-carboxylic acidethyl ester 68 can be synthesized as described in the literature(Journal of Organic Chemistry 1975, 40, 2341-2346). Alkylation of 68 canbe achieved by standard basic alkylation conditions incorporating alkylhalides, with one equivalent of the appropriate alkyl halide and base togive a mixture of the N-alkyl pyrazinone 65 (R⁹ is H) and theregioisomeric O-alkyl pyrazine, which can be separated by columnchromatography. These conditions include but are not limited to K₂CO₃ inacetone or DMF at room or elevated temperature or NaH in THF at ambientor elevated temperature and then addition of the alkyl halide.

FIG. 24 depicts the synthesis of the aminopyrazinone core where R⁹ isMe. 3-Amino-6-methylpyrazine-2-carboxylic acid ethyl ester N-oxide 69can be synthesized as described in the literature (J. HeterocyclicChemistry 1987, 24, 1621-1628). Rearrangement of N-oxide 69 can beachieved with either acetic anhydride and acetic acid or trifluoroaceticanhydride and trifluoroacetic acid, which is then followed bydeprotection with MeOH or EtOH to provide 70. Alkylation of 70 can beachieved by standard basic alkylation conditions incorporating alkylhalides, with one equivalent of the appropriate alkyl halide and base togive a mixture of the N-alkyl pyrazinone 65 (R⁹ is Me) and theregioisomeric O-alkyl pyrazine, which can be separated by columnchromatography. These conditions include but are not limited to K₂CO₃ inacetone or DMF at room or elevated temperature or NaH in THF at ambientor elevated temperature and then addition of the alkyl halide.

FIG. 25 also depicts the synthesis of the aminopyrazinone core whereR⁹=Me. 3-Amino-5-chloro-6-methylpyrazine-2-carbonitrile 71 can besynthesized as described in the literature (J. Heterocyclic Chemistry1987, 24, 1621-1628). Pyrazinone 72 can be made in a two step sequence.In the first step, pyrazine 71 is treated with sodium methoxide in asuitable organic solvent such as MeOH or THF or MeOH/THF mixtures attemperatures ranging from 0° C. to reflux. Demethylation of the methoxypyrazine to provide 72 can then be accomplished by standard conditionsincluding but not limited to pTsOH in acetic acid at elevatedtemperature or aqueous HBr in MeOH at elevated temperature. Alkylationof 72 can be achieved by standard basic alkylation conditionsincorporating alkyl halides, with one equivalent of the appropriatealkyl halide and base to give a mixture of the N-alkyl pyrazinone 73 andthe regioisomeric O-alkyl pyrazine, which can be separated by columnchromatography. These conditions include but are not limited to K₂CO₃ inacetone or DMF at room or elevated temperature or NaH in THF at ambientor elevated temperature and then addition of the alkyl halide.Hydrolysis of nitrile 73 is followed by esterification to give ester 65(R⁹=Me). Hydrolysis of the nitrile can be achieved with either an acidicor basic aqueous solution, including but not limited to aqueous HCl,KOH, or NaOH. Esterification to give the methyl ester 65 (R⁹ is Me) canbe carried out under standard conditions, including but not limited toFisher esterification (MeOH, H₂SO₄), TMSCl in MeOH or TMSCHN₂ insuitable organic solvents such as PhMe/MeOH.

FIG. 26 depicts the synthesis of the aminopyrazinone core where R⁹ isC(═O)H. A protected oxime analog,3-amino-6-(benzyliminomethyl)-pyrazine-2-carboxylic acid ethyl esterN-oxide 74 can be synthesized as described in the literature (JustusLiebigs Annalen der Chemie 1969, 726, 100-102), with the use ofO-benzyl-hydroxylamine in place of hydroxylamine. Protection of theoxime functionality with a standard protecting group includes, but isnot limited to O-benzyl. This is followed by rearrangement of N-oxide 74with either acetic anhydride and acetic acid or trifluoroaceticanhydride and trifluoroacetic acid. Removal of the N-acyl functionalityof 75 can be achieved with MeOH or EtOH to provide 76. Alkylation of 76can be achieved by standard basic alkylation conditions incorporatingalkyl halides, with one equivalent of the appropriate alkyl halide andbase to give a mixture of the N-alkyl pyrazinone 77 and theregioisomeric O-alkyl pyrazine, which can be separated by columnchromatography. These conditions include but are not limited to K₂CO₃ inacetone or DMF at room or elevated temperature or NaH in THF at ambientor elevated temperature and then addition of the alkyl halide.Deprotection of oxime 77 is followed by its cleavage to the aldehyde 65(R⁹═C(O)H). Deprotection of the oxime depends on the nature of theprotecting group chosen. If the protecting group chosen is benzyl, itcan be removed under catalytic hydrogenation conditions with a suitablePd or Pt catalyst, including but not limited to Pd—C or PtO₂ under anatmosphere of hydrogen in a suitable organic solvent. Conversion ofoxime to aldehyde 65 (R⁹═C(O)H) can be achieved under hydrolysisconditions, including but not limited to aqueous HCl in an appropriateorganic solvent such as dioxane.

FIG. 27 depicts the synthesis of the aminopyrazinone core where R⁹ isCl. 3-Amino-6-chloro-5-oxo-4,5-dihydropyrazine-2-carboxylic acid methylester 78 can be synthesized as described in the literature (J. MedicinalChemistry 1967, 10, 66-75). Alkylation of 78 can be achieved by standardbasic alkylation conditions incorporating alkyl halides, with oneequivalent of the appropriate alkyl halide and base to give a mixture ofthe N-alkyl pyrazinone 65 (R⁹=Cl) and the regioisomeric O-alkylpyrazine, which can be separated by column chromatography. Theseconditions include but are not limited to K₂CO₃ in acetone or DMF atroom or elevated temperature or NaH in THF at ambient or elevatedtemperature and then addition of the alkyl halide.

In FIG. 28, the synthesis of compounds of Formula V is depicted, where Xis N. The conversion of chloride 79 to compounds 61 where R⁹ can bearyl, heteroaryl, alkyl, cycloalkyl, alkenyl, alkynyl, amino or anilinocan be achieved using Pd mediated cross-coupling conditions. In general,this chemistry can be accomplished using a wide variety of Pd catalystsand ligands, with or without added base, in a suitable organic solventsuch as DMF, PhMe, DME, THF, CH₃CN at elevated temperature. The couplingpartner will depend on the nature of R⁹. These Pd mediated crosscouplings are well documented in the literature and are known by anyoneskilled in the art. When R⁹ is alkenyl or alkynyl, these can be furtherreduced using the appropriate reducing agent to provide alkylsubstituents at R⁹.

FIGS. 29-32 depict the synthesis of compounds of Formula V, where X isN. In these syntheses, aldehyde 61 (R⁹═C(O)H) is converted to variousother functionalities. FIG. 29 depicts the conversion of aldehyde 61 toamine 80. This can be accomplished by reductive amination, whichinvolves the reaction of the aldehyde with the desired amine and AcOH,followed by reduction with a suitable reducing agent, including but notlimited to Me₄NBH(OAc)₃, in a suitable organic solvent such as CH₃CN atambient temperature. Carboxylic acid 62, as well as hydroxamate 63 andamide 64, where R⁹ is equal to CH₂NR³R⁴, can then be prepared from 80 asdescribed in FIGS. 19 and 20.

FIG. 30 depicts the conversion of aldehyde 61 (R⁹═C(O)H) to alcohol 81and ether 82. Reduction of aldehyde 61 (R⁹═C(O)H) with a suitablereducing agent, including but not limited to NaBH₄, provides alcohol 81.Alcohol 81 can be converted to ether 82 by reaction with a suitable baseand the desired alkyl halide, including but not limited to addition ofNaH to alcohol 81 and the then addition of an alkyl bromide or alkyliodide. Alcohol 81 can also be converted to ether 82 by halogenation oractivation followed by addition of a desired alcohol. Halogenation canbe accomplished with POCl₃, thionyl chloride, oxalyl chloride, PCl₅,PBr₃, or Ph₃P and Br₂, and activation can be achieved by reaction ofaldehyde 61 (R⁹═C(O)H) with, including but not limited to, MsCl or TsCl.Both halogenation and activation steps are followed by addition of adesired alcohol to yield 82. Carboxylic acid 62, as well as hydroxamate63 and amide 64, where R⁹ is CH₂OH or CH₂OR, can then be prepared from81 or 82 as described in FIGS. 19 and 20.

FIG. 31 depicts the conversion of aldehyde 61 (R⁹═C(O)H) to amide 84.Oxidation of aldehyde 61 (R⁹═C(O)H) with a suitable oxidizing agent,including but not limited to KMnO₄, CrO₃ or Na₂Cr₂O₇, can providecarboxylic acid 83. Conversion of acid 83 to amide 84 can beaccomplished using standard coupling procedures, including but notlimited to EDCI, HOBt, or PyBOP and the appropriate amine in suitableorganic solvents such as DMF, THF, or methylene chloride. In someinstances, the amine used in the coupling reaction contains a standardprotecting group. In those cases, the protecting group can be removed bystandard conditions known in the art. Carboxylic acid 62, as well ashydroxamate 63 and amide 64, where R⁹ is equal to C(O)NR³R⁴, can then beprepared from 84 as described in FIGS. 19 and 20.

FIG. 32 depicts the conversion of aldehyde 61 (R⁹═C(O)H) to alkyl 85.Reaction of aldehyde 61 (R⁹═C(O)H) under standard Wittig reactionconditions, followed by reduction of the resulting alkene can providealkyl 85. The Wittig reaction involves the addition of a desiredphosphorous ylide, R₂C—P(C₆H₅)₃, to the aldehyde in a suitable organicsolvent such as THF. The conditions for formation of the desiredphosphorous ylide are well documented in the literature and are known byanyone skilled in the art. Reduction of the alkene to provide 85 can beaccomplished under a hydrogen atmosphere with a suitable catalyst, suchas PtO₂ or Pd/C. Carboxylic acid 62, as well as hydroxamate 63 and amide64, where R₉ is equal to CH₂CR₂, can then be prepared from 85 asdescribed in FIGS. 19 and 20.

In FIG. 33, the synthesis of compounds of Formula V is depicted where Wis heterocyclic. Carboxylic acid 55 or 62 can be converted to hydrazide86 using standard coupling procedures, including but not limited toEDCI, HOBt, or PyBOP and hydrazine in suitable organic solvents such asDMF, THF, or methylene chloride. Hydrazide 86 can then be converted toseveral desired heterocyclic analogs by cyclization with an appropriatereagent. Conversion of 86 to amino oxadiazole 87 can be accomplishedusing cyanogen bromide and a base such as NaHCO₃, in a suitable biphasicsolvent system such as dioxane and water at room temperature. Conversionof 86 to the oxadiazolone 88 can be accomplished by reaction withphosgene, CDI, or a phosgene equivalent. Conversion of 86 to the aminotriazole 89 can be accomplished in a two step procedure, first byreaction with NH₃CN and aqueous HCl, followed by cyclization withtriphenylphosphine, triethylamine and carbon tetrachloride. Conversionof 86 to the methyl trizole 90 can be accomplished in a two stepprocedure, first by reaction with an appropriate coupling agent, such ascyanamide or ethyl acetimidate, followed by cyclization withtriphenylphosphine, triethylamine and carbon tetrachloride indichloromethane. Finally, conversion of carboxylic acid 55 or 62 to theaminothiazole 91 can be accomplished with thiosemicarbazide usingstandard coupling conditions, such as EDCI, followed by cyclization withtriphenylphosphine, triethylamine and carbon tetrachloride indichloromethane.

In FIG. 34, the synthesis of compounds of Formula V is depicted where Wis heterocyclic. Ring opening of oxadiazolone 88 with a desired aminecan be accomplished in EtOH under refluxing conditions to yield 92,which can be recyclized to 93 with triphenylphosphine, triethylamine andcarbon tetrachloride in dichloromethane. In some instances, the amineused in the ring-opening reaction can contain a standard protectinggroup. In those cases, the protecting group can be removed by standardconditions known in the art.

The invention also relates to a pharmaceutical composition for thetreatment of a hyperproliferative disorder in a mammal which comprises atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, prodrug or hydrate thereof, and apharmaceutically acceptable carrier. In one embodiment, saidpharmaceutical composition is for the treatment of cancer such as brain,lung, squamous cell, bladder, gastic, pancreatic, breast, head, neck,renal, kidney, ovarian, prostate, colorectal, esophageal, testicular,gynecological or thyroid cancer. In another embodiment, saidpharmaceutical composition is for the treatment of a non-canceroushyperproliferative disorder such as benign hyperplasia of the skin(e.g., psoriasis), restenosis, or prostate (e.g., benign prostatichypertrophy (BPH)).

The invention also relates to a pharmaceutical composition for thetreatment of pancreatitis or kidney disease (including proliferativeglomerulonephritis and diabetes-induced renal disease) or the treatmentof pain in a mammal which comprises a therapeutically effective amountof a compound of the present invention, or a pharmaceutically acceptablesalt, prodrug or hydrate thereof, and a pharmaceutically acceptablecarrier.

The invention also relates to a pharmaceutical composition for theprevention of blastocyte implantation in a mammal which comprises atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, prodrug or hydrate thereof, and apharmaceutically acceptable carrier.

The invention also relates to a pharmaceutical composition for treatinga disease related to vasculogenesis or angiogenesis in a mammal whichcomprises a therapeutically effective amount of a compound of thepresent invention, or a pharmaceutically acceptable salt, prodrug orhydrate thereof, and a pharmaceutically acceptable carrier. In oneembodiment, said pharmaceutical composition is for treating a diseaseselected from the group consisting of tumor angiogenesis, chronicinflammatory disease or other inflammatory condition such as rheumatoidarthritis, atherosclerosis, inflammatory bowel disease, skin diseasessuch as psoriasis, eczema, and scleroderma, diabetes, diabeticretinopathy, retinopathy of prematurity, age-related maculardegeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma andovarian, breast, lung, pancreatic, prostate, colon and epidermoidcancer.

The invention also relates to a method of treating a hyperproliferativedisorder in a mammal that comprises administering to said mammal atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, prodrug or hydrate thereof. Inone embodiment, said method relates to the treatment of cancer such asbrain, lung, squamous cell, bladder, gastic, pancreatic, breast, head,neck, renal, kidney, ovarian, prostate, colorectal, esophageal,testicular, gynecological or thyroid cancer. In another embodiment, saidmethod relates to the treatment of a non-cancerous hyperproliferativedisorder such as benign hyperplasia of the skin (e.g., psoriasis),restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH)).

The invention also relates to a method for the treatment of ahyperproliferative disorder in a mammal that comprises administering tosaid mammal a therapeutically effective amount of a compound of thepresent invention, or a pharmaceutically acceptable salt, prodrug orhydrate thereof, in combination with an anti-tumor agent selected fromthe group consisting of mitotic inhibitors, alkylating agents,anti-metabolites, intercalating antibiotics, growth factor inhibitors,cell cycle inhibitors, enzyme inhibitors, topoisomerase inhibitors,biological response modifiers, anti-hormones, angiogenesis inhibitors,and anti-androgens.

The invention also relates to a method of treating pancreatitis orkidney disease in a mammal that comprises administering to said mammal atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, prodrug or hydrate thereof.

The invention also relates to a method of preventing blastocyteimplantation in a mammal that comprises administering to said mammal atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, prodrug or hydrate thereof.

The invention also relates to a method of treating diseases related tovasculogenesis or angiogenesis in a mammal that comprises administeringto said mammal a therapeutically effective amount of a compound of thepresent invention, or a pharmaceutically acceptable salt, prodrug orhydrate thereof. In one embodiment, said method is for treating adisease selected from the group consisting of tumor angiogenesis,chronic inflammatory disease such as rheumatoid arthritis,atherosclerosis, inflammatory bowel disease, skin diseases such aspsoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy,retinopathy of prematurity, age-related macular degeneration,hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast,lung, pancreatic, prostate, colon and epidermoid cancer.

The invention also relates to a pharmaceutical composition for treatinga disease or condition related to inflammatory disease, autoimmunedisease, destructive bone disorders, proliferative disorders, infectiousdisease, viral disease, fibrotic disease or neurodegenerative disease ina mammal which comprises a therapeutically effective amount of acompound of the present invention, or a pharmaceutically acceptablesalt, prodrug or hydrate thereof, and a pharmaceutically acceptablecarrier. Examples of the above diseases and/or conditions include but isnot limited to rheumatoid arthritis, atherosclerosis, inflammatory boweldisease, skin diseases such as psoriasis, eczema, and scleroderma,diabetes and diabetic complications, diabetic retinopathy, retinopathyof prematurity, age-related macular degeneration, hemangioma, chronicobstructive pulmonary disease, idiopathic pulmonary fibrosis, allergicresponses including asthma allergic rhinitis and atopic dermatitis,renal disease and renal failure, polycystic kidney disease, acutecoronary syndrome, congestive heart failure, osteoarthritis,neurofibromatosis, organ transplant rejection, cachexia and pain.

Further provided is a compound of Formula I, Formula II, Formula III,Formula IV or Formula V for use as a medicament in the treatment of thediseases and conditions described above in a warm-blooded animal,preferably a mammal, more preferably a human, suffering from suchdisorder. Also provided is the use of a compound of Formula I, FormulaII, Formula III, Formula IV or Formula V in the preparation of amedicament for the treatment of the diseases and conditions describedabove in a warm-blooded animal, preferably a mammal, more preferably ahuman, suffering from such disorder.

Patients that can be treated with compounds of the present invention, orpharmaceutically acceptable salts, prodrugs and hydrates of saidcompounds, according to the methods of this invention include, forexample, patients that have been diagnosed as having psoriasis,restenosis, atherosclerosis, BPH, lung cancer, bone cancer, CMML,pancreatic cancer, skin cancer, cancer of the head and neck, cutaneousor intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer,cancer of the anal region, stomach cancer, colon cancer, breast cancer,testicular, gynecologic tumors (e.g., uterine sarcomas, carcinoma of thefallopian tubes, carcinoma of the endometrium, carcinoma of the cervix,carcinoma of the vagina or carcinoma of the vulva), Hodgkin's disease,cancer of the esophagus, cancer of the small intestine, cancer of theendocrine system (e.g., cancer of the thyroid, parathyroid or adrenalglands), sarcomas of soft tissues, cancer of the urethra, cancer of thepenis, prostate cancer, chronic or acute leukemia, solid tumors ofchildhood, lymphocytic lymphomas, cancer of the bladder, cancer of thekidney or ureter (e.g., renal cell carcinoma, carcinoma of the renalpelvis), or neoplasms of the central nervous system (e.g., primary CNSlymphoma, spinal axis tumors, brain stem gliomas or pituitary adenomas).

This invention also relates to a pharmaceutical composition forinhibiting abnormal cell growth in a mammal which comprises an amount ofa compound of the present invention, or a pharmaceutically acceptablesalt or solvate or prodrug thereof, in combination with an amount of achemotherapeutic, wherein the amounts of the compound, salt, solvate, orprodrug, and of the chemotherapeutic are together effective ininhibiting abnormal cell growth. Many chemotherapeutics are presentlyknown in the art. In one embodiment, the chemotherapeutic is selectedfrom the group consisting of mitotic inhibitors, alkylating agents,anti-metabolites, intercalating antibiotics, growth factor inhibitors,cell cycle inhibitors, enzymes, topoisomerase inhibitors, biologicalresponse modifiers, anti-hormones, angiogenesis inhibitors, andanti-androgens.

This invention further relates to a method for inhibiting abnormal cellgrowth in a mammal or treating a hyperproliferative disorder whichmethod comprises administering to the mammal an amount of a compound ofthe present invention, or a pharmaceutically acceptable salt or solvateor prodrug thereof, in combination with radiation therapy, wherein theamounts of the compound, salt, solvate, or prodrug, is in combinationwith the radiation therapy effective in inhibiting abnormal cell growthor treating the hyperproliferative disorder in the mammal. Techniquesfor administering radiation therapy are known in the art, and thesetechniques can be used in the combination therapy described herein. Theadministration of the compound of the invention in this combinationtherapy can be determined as described herein.

It is believed that the compounds of the present invention can renderabnormal cells more sensitive to treatment with radiation for purposesof killing and/or inhibiting the growth of such cells. Accordingly, thisinvention further relates to a method for sensitizing abnormal cells ina mammal to treatment with radiation which comprises administering tothe mammal an amount of a compound of the present invention orpharmaceutically acceptable salt or solvate or prodrug thereof, whichamount is effective is sensitizing abnormal cells to treatment withradiation. The amount of the compound, salt, or solvate in this methodcan be determined according to the means for ascertaining effectiveamounts of such compounds described herein.

The invention also relates to a method of and to a pharmaceuticalcomposition of inhibiting abnormal cell growth in a mammal whichcomprises an amount of a compound of the present invention, or apharmaceutically acceptable salt or solvate thereof, a prodrug thereof,or an isotopically-labeled derivative thereof, and an amount of one ormore substances selected from anti-angiogenesis agents, signaltransduction inhibitors, and antiproliferative agents.

Anti-angiogenesis agents, such as MMP-2 (matrix-metalloprotienase 2)inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-II(cyclooxygenase II) inhibitors, can be used in conjunction with acompound of the present invention and pharmaceutical compositionsdescribed herein. Examples of useful COX-II inhibitors include CELEBREX™(alecoxib), valdecoxib, and rofecoxib. Examples of useful matrixmetalloprotienase inhibitors are described in WO 96/33172, WO 96/27583,EP 818442, EP 1004578, WO 98/07697, WO 98/03516, WO 98/34918, WO98/34915, WO 98/33768, WO 98/30566, EP 606,046, EP 931,788, WO 90/05719,WO 99/52910, WO 99/52889, WO 99/29667, WO 99/07675, EP 945864, U.S. Pat.No. 5,863,949, U.S. Pat. No. 5,861,510, and EP 780,386, all of which areincorporated herein in their entireties by reference. Preferred MMP-2and MMP-9 inhibitors are those that have little or no activityinhibiting MMP-1. More preferred, are those that selectively inhibitMMP-2 and/or MMP-9 relative to the other matrix-metalloproteinases(i.e., MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11,MMP-12, and MMP-13).

The terms “abnormal cell growth” and “hyperproliferative disorder” areused interchangeably in this application.

“Abnormal cell growth,” as used herein, unless otherwise indicated,refers to cell growth that is independent of normal regulatorymechanisms (e.g., loss of contact inhibition). This includes, forexample, the abnormal growth of: (1) tumor cells (tumors) thatproliferate by expressing a mutated tyrosine kinase or over-expressionof a receptor tyrosine kinase; (2) benign and malignant cells of otherproliferative diseases in which aberrant tyrosine kinase activationoccurs; (3) any tumors that proliferate by receptor tyrosine kinases;(4) any tumors that proliferate by aberrant serine/threonine kinaseactivation; and (5) benign and malignant cells of other proliferativediseases in which aberrant serine/theroine kinase activation occurs.

The term “treating,” as used herein, unless otherwise indicated, meansreversing, alleviating, inhibiting the progress of, or preventing thedisorder or condition to which such term applies, or one or moresymptoms of such disorder or condition. The term “treatment,” as usedherein, unless otherwise indicated, refers to the act of treating as“treating” is defined immediately above.

The amount of a given agent that will correspond to such an amount willvary depending upon factors such as the particular compound, diseasecondition and its severity, the identity (e.g., weight) of the mammal inneed of treatment, but can nevertheless be routinely determined by oneskilled in the art. “Treating” is intended to mean at least themitigation of a disease condition in a mammal, such as a human, that isaffected, at least in part, by the activity of MEK, and includes, but isnot limited to, preventing the disease condition from occurring in amammal, particularly when the mammal is found to be predisposed tohaving the disease condition but has not yet been diagnosed as havingit; modulating and/or inhibiting the disease condition; and/oralleviating the disease condition.

In order to use a compound of the Formula I-V or a pharmaceuticallyacceptable salt or prodrug thereof, for the therapeutic treatment(including prophylactic treatment) of mammals including humans, it isnormally formulated in accordance with standard pharmaceutical practiceas a pharmaceutical composition. According to this aspect of theinvention there is provided a pharmaceutical composition that comprisesa compound of the Formula I-V, or a pharmaceutically acceptable salt orprodrug thereof, as defined hereinbefore in association with apharmaceutically acceptable diluent or carrier.

To prepare the pharmaceutical compositions according to this invention,a therapeutically or prophylactically effective amount of a compound ofFormula I-V or a pharmaceutically acceptable salt, solvate, metaboliteor prodrug thereof (alone or together with an additional therapeuticagent) is preferably intimately admixed with a pharmaceuticallyacceptable carrier according to conventional pharmaceutical compoundingtechniques to produce a dose. A carrier may take a wide variety of formsdepending on the form of preparation desired for administration, e.g.,oral or parenteral. Examples of suitable carriers include any and allsolvents, dispersion media, adjuvants, coatings, antibacterial andantifungal agents, isotonic and absorption delaying agents, sweeteners,stabilizers (to promote long term storage), emulsifiers, binding agents,thickening agents, salts, preservatives, solvents, dispersion media,coatings, antibacterial and antifungal agents, isotonic and absorptiondelaying agents, flavoring agents, and miscellaneous materials such asbuffers and absorbents that may be needed in order to prepare aparticular therapeutic composition. The use of such media and agentswith pharmaceutically active substances is well known in the art. Exceptinsofar as any conventional media or agent is incompatible with acompound of Formula I-V, its use in the therapeutic compositions andpreparations is contemplated. Supplementary active ingredients can alsobe incorporated into the compositions and preparations as describedherein.

The compositions of the invention may be in a form suitable for oral use(for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous, or intramusculardosing or as a suppository for rectal dosing). For example, compositionsintended for oral use may contain, for example, one or more coloring,sweetening, flavoring and/or preservative agents.

Suitable pharmaceutically-acceptable excipients for a tablet formulationinclude, for example, inert diluents such as lactose, sodium carbonate,calcium phosphate or calcium carbonate, granulating and disintegratingagents such as corn starch or algenic acid; binding agents such asstarch; lubricating agents such as magnesium stearate, stearic acid ortalc; preservative agents such as ethyl or propyl p-hydroxybenzoate, andanti-oxidants, such as ascorbic acid. Tablet formulations may beuncoated or coated either to modify their disintegration and thesubsequent absorption of the active ingredient within thegastrointestinal tract, or to improve their stability and/or appearance,in either case, using conventional coating agents and procedures wellknown in the art.

Compositions for oral use may be in the form of hard gelatin capsules inwhich the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules in which the active ingredient is mixed with water oran oil such as peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions generally contain the active ingredient in finelypowdered form together with one or more suspending agents, such assodium carboxymethylcellulose. methylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone,gum tragacanth and gum acacia; dispersing or wetting agents such aslecithin or condensation products of an alkylene oxide with fatty acids(for example polyoxethylene stearate), or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example polyethylene sorbitan monooleate. The aqueoussuspensions may also contain one or more preservatives (such as ethyl orpropyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid),coloring agents, flavoring agents, and/or sweetening agents (such assucrose, saccharine or aspartame).

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil (such as arachis oil, olive oil, sesame oil orcoconut oil) or in a mineral oil (such as liquid paraffin). The oilysuspensions may also contain a thickening agent such as beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set outabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water generally contain the activeingredient together with a dispersing or wetting agent, suspending agentand one or more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients such as sweetening, flavoring and coloring agents,may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, or a mineral oil, such as for exampleliquid paraffin or a mixture of any of these. Suitable emulsifyingagents may be, for example, naturally-occurring gums such as gum acaciaor gum tragacanth, naturally-occurring phosphatides such as soya bean,lecithin, an esters or partial esters derived from fatty acids andhexitol anhydrides (for example sorbitan monooleate) and condensationproducts of the said partial esters with ethylene oxide such aspolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening, flavoring and preservative agents.

Syrups and elixirs may be formulated with sweetening agents such asglycerol, propylene glycol, sorbitol, aspartame or sucrose, and may alsocontain a demulcent, preservative, flavoring and/or coloring agent.

The pharmaceutical compositions may also be in the form of a sterileinjectable aqueous or oily suspension, which may be formulated accordingto known procedures using one or more of the appropriate dispersing orwetting agents and suspending agents, which have been mentioned above. Asterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally-acceptable diluent or solvent,for example a solution in 1,3-butanediol.

Suppository formulations may be prepared by mixing the active ingredientwith a suitable non-irritating excipient which is solid at ordinarytemperatures but liquid at the rectal temperature and will thereforemelt in the rectum to release the drug. Suitable excipients include, forexample, cocoa butter and polyethylene glycols.

Topical formulations, such as creams, ointments, gels and aqueous oroily solutions or suspensions, may generally be obtained by formulatingan active ingredient with a conventional, topically acceptable, vehicleor diluent using conventional procedures well known in the art.

Compositions for administration by insufflation may be in the form of afinely divided powder containing particles of average diameter of, forexample, 30 μm or much less, the powder itself comprising either activeingredient alone or diluted with one or more physiologically acceptablecarriers such as lactose. The powder for insufflation is thenconveniently retained in a capsule containing, for example, 1 to 50 mgof active ingredient for use with a turbo-inhaler device, such as isused for insufflation of the known agent sodium cromoglycate.

Compositions for administration by inhalation may be in the form of aconventional pressurized aerosol arranged to dispense the activeingredient either as an aerosol containing finely divided solid orliquid droplets. Conventional aerosol propellants such as volatilefluorinated hydrocarbons or hydrocarbons may be used and the aerosoldevice is conveniently arranged to dispense a metered quantity of activeingredient.

For further information on formulations, see Chapter 25.2 in Volume 5 ofComprehensive Medicinal Chemistry (Corwin Hansch; Chairman of EditorialBoard), Pergamon Press 1990, which is specifically incorporated hereinby reference.

The amount of a compound of this invention that is combined with one ormore excipients to produce a single dosage form will necessarily varydepending upon the subject treated, the severity of the disorder orcondition, the rate of administration, the disposition of the compoundand the discretion of the prescribing physician. However, an effectivedosage is in the range of about 0.001 to about 100 mg per kg body weightper day, preferably about 1 to about 35 mg/kg/day, in single or divideddoses. For a 70 kg human, this would amount to about 0.05 to 7 g/day,preferably about 0.05 to about 2.5 g/day. In some instances, dosagelevels below the lower limit of the aforesaid range may be more thanadequate, while in other cases still larger doses may be employedwithout causing any harmful side effect, provided that such larger dosesare first divided into several small doses for administration throughoutthe day. For further information on routes of administration and dosageregimes, see Chapter 25.3 in Volume 5 of Comprehensive MedicinalChemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press1990, which is specifically incorporated herein by reference.

The size of the dose for therapeutic or prophylactic purposes of acompound of Formula I-V will naturally vary according to the nature andseverity of the conditions, the age and sex of the animal or patient andthe route of administration, according to well known principles ofmedicine.

The compounds of this invention may be used alone in combination withother drugs and therapies used in the treatment of disease states whichwould benefit from the inhibition of MEK. Such treatment may involve, inaddition to the compounds of the invention, conventional surgery orradiotherapy or chemotherapy. Such chemotherapy may include one or moreof the following categories of anti-tumor agents:

(i) antiproliferative/anti-neoplastic drugs and combinations thereof, asused in medical oncology, such as alkylating agents (for example,cis-platin, carboplatin, cyclophosphamide, nitorgen mustard, melphalan,chlorambucil, busulphan and nitorsoureas); anti-metabolites (forexample, antifolates such as such as fluoropyrimidines like5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosinearabinside, hydroxyurea, or, one of the preferred anti-metabolitesdisclosed in European Patent Application No. 239362 such asN-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamicacid); antitumor antibiotics (for example, anthracyclines likeadriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin,mitomycin-C, dactinomycin and mithramycin); antimitotic agents (forexample, vinca alkaloids like vincristine, vinblastine, vindesine andvinorelbine and taxoids like taxol and taxotere); and topoisomeraseinhibitors (for example epipodophyllotoxins like eptoposide andteniposide, amsacrine, topotecan and campothecin):

(ii) cytostatic agents such as antiestrogens (for example, tamoxifen,toremifene, raloxifene, droloxifene and iodoxyfene), estrogen receptordown regulators (for example, fulvestratrant) antiandrogens (forexample, bicalutamide, flutamide, nilutamide, cyproxerone acetate andCasodex™(4′-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3′-(trifluoromethyl)propionanilide)),LHRH antagonists or LHRH agonists (for example, goserelin, leuporelinand buserelin), progestogens (for example, megestrol acetate), aromataseinhibitors (for example, asanastrozole, letrozole, vorazole andexemestane) and inhibitors of 5α-reductase such as finasteride;

(iii) agents which inhibit cancer cell invasion (for example,metalloproteinase inhibitors like marimastat and inhibitors of urokinaseplasminogne activator receptor function);

(iv) inhibitors of growth factor function like growth factor antibodies,growth factor receptor antibodies (for example, the anti-erbB2 antibodytrastumuzab [Herceptin™] and the anti-erbB1 antibody cetuximab [C225]),farnesyl transferase inhibitors, tyrosine kinase inhibitors andserine-threonine kinase inhibitors (for example, inhibitors of theepidermal growth factor family tyrosine kinases such asN-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine(gefitinib, AZD1839),N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine(erlotinib, OSI-774) and6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine(CI-1033)), inhibitors of the platelet-derived growth factor family andinhibitors of the hepatocyte growth factor family;

(v) antiangiogenic agents such as those which inhibit the effects ofvascular endothelial growth factor (for example, the anti-vascularendothelial cell growth factor antibody bevacizumab [Avastin™],compounds such as those disclosed in PCT Publication Nos. WO 97/22596,WO 97/30035, WO 97/32856, and WO 98/13354) and compounds that work byother mechanisms (for example, linomide, inhibitors of integrin αvβ3function, MMP inhibitors, COX-2 inhibitors and angiostatin);

(vi) vascular damaging agents such as Combretastatin A4 and compoundsdisclosed in PCT Publication Nos. WO 99/02166, WO 0/40529, WO 00/41669,WO 01/92224, WO 02/04434, and WO 02/08213;

(vii) antisense therapies (for example, those which are directed to thetargets listed above such as ISIS 2503, and anti-ras antisense);

(viii) gene therapy approaches, including for example GVAX™, approachesto replace aberrant genes such as aberrant p53 or aberrant BRCA1 orBRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such asthose using cytosine deaminase, thymidine kinase or a bacterialnitroreductase enzyme and approaches to increase patient tolerance tochemotherapy or radiotherapy such as multi-drug resistance gene therapy;

(ix) interferon; and

(x) immunotherapy approaches, including for example ex-vivo and in-vivoapproaches to increase the immunogenicity of patient tumor cells, suchas transfection with cytokines such as interleukin 2, interleukin 4 orgranulocyte-macrophage colony stimulating factor, approaches to decreaseT-cell anergy, approaches to using transfected immune cells such ascytokine-transfected dendritic cells, approaches usingcytokine-transfected tumor cell lines and approaches usinganti-idiotypic antibodies.

Such conjoint treatment may be achieved by way of the simultaneous,sequential or separate dosing of the individual components of treatment.Such combination products employ the compounds of this invention withinthe dose range described hereinbefore and the other pharmaceuticallyactive agent within its approved dose range.

According to this aspect of the invention there is provided apharmaceutical product comprising a compound of Formula I-V as definedhereinbefore and an additional anti-tumor agent as defined hereinbeforefor the conjoint treatment of cancer.

Although the compounds of Formula I-V are primarily of value astherapeutic agents for use in warm-blooded animals (including man), theyare also useful whenever it is required to inhibit the effects of MEK.Thus, they are useful as pharmacological standards for use in thedevelopment of new biological tests and in the search for newpharmacological agents.

The activity of the compounds of the present invention may be determinedby the following procedure. N-terminal 6 His-tagged, constitutivelyactive MEK-1 (2-393) is expressed in E. coli and protein is purified byconventional methods (Ahn et al, Science 1994, 265, 966-970). Theactivity of MEK1 is assessed by measuring the incorporation ofγ-³³P-phosphate from γ-³³P-ATP onto N-terminal His tagged ERK2, which isexpressed in E. coli and is purified by conventional methods, in thepresence of MEK-1. The assay is carried out in 96-well polypropyleneplate. The incubation mixture (100 μL) comprises of 25 mM Hepes, pH 7.4,10 mM MgCl₂, 5 mM β-glycerolphosphate, 100 μM Na-orthovanadate, 5 mMDTT, 5 nM MEK1, and 1 μM ERK2. Inhibitors are suspended in DMSO, and allreactions, including controls are performed at a final concentration of1% DMSO. Reactions are initiated by the addition of 10 μM ATP (with 0.5μCi γ-³³P-ATP/well) and incubated at ambient temperature for 45 minutes.Equal volume of 25% TCA is added to stop the reaction and precipitatethe proteins. Precipitated proteins are trapped onto glass fiber Bfilterplates, and excess labeled ATP washed off using a Tomtec MACH IIIharvestor. Plates are allowed to air-dry prior to adding 30 μL/well ofPackard Microscint 20, and plates are counted using a Packard TopCount.In this assay, compounds of the invention exhibited an IC₅₀ of less than50 micromolar.

Representative compounds of the present invention, which are encompassedby the present invention include, but are not limited to the compoundsof the examples and their pharmaceutically acceptable acid or baseaddition salts or prodrugs thereof. The examples presented below areintended to illustrate particular embodiments of the invention, and arenot intended to limit the scope of the specification or the claims inany way.

The disclosures in this application of all articles and references,including patents, are incorporated herein by reference.

EXAMPLES

In order to illustrate the invention, the following examples areincluded. However, it is to be understood that these examples do notlimit the invention and are only meant to suggest a method of practicingthe invention. Persons skilled in the art will recognize that thechemical reactions described may be readily adapted to prepare a numberof other MEK inhibitors of the invention, and alternative methods forpreparing the compounds of this invention are deemed to be within thescope of this invention. For example, the synthesis of non-exemplifiedcompounds according to the invention may be successfully performed bymodifications apparent to those skilled in the art, e.g., byappropriately protecting interfering groups, by utilizing other suitablereagents known in the art other than those described, and/or by makingroutine modifications of reaction conditions. Alternatively, otherreactions disclosed herein or known in the art will be recognized ashaving applicability for preparing other compounds of the invention.

In the examples described below, unless otherwise indicated alltemperatures are set forth in degrees Celsius. Reagents were purchasedfrom commercial suppliers such as Aldrich Chemical Company, Lancaster,TCI or Maybridge, and were used without further purification unlessotherwise indicated. Tetrahydrofuran (THF), N,N-dimethylformamide (DMF),dichloromethane, toluene, dioxane and 1,2-difluoroethane were purchasedfrom Aldrich in Sure seal bottles and used as received.

The reactions set forth below were done generally under a positivepressure of nitrogen or argon or with a drying tube (unless otherwisestated) in anhydrous solvents, and the reaction flasks were typicallyfitted with rubber septa for the introduction of substrates and reagentsvia syringe. Glassware was oven dried and/or heat dried.

Column chromatography was done on a Biotage system (Manufacturer: DyaxCorporation) having a silica gel column or on a silica SepPak cartridge(Waters).

¹H-NMR spectra were recorded on a Varian instrument operating at 400MHz. ¹H-NMR spectra were obtained as CDCl₃ solutions (reported in ppm),using chloroform as the reference standard (7.25 ppm). Other NMRsolvents were used as needed. When peak multiplicities are reported, thefollowing abbreviations are used: s (singlet), d (doublet), t (triplet),m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet oftriplets). Coupling constants, when given, are reported in Hertz (Hz).

Example 1

4-(4-Bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid

Step A: Preparation of4-hydroxy-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethylester: Triethyl orthoformate (45.82 mL, 275.5 mmol) and acetic anhydride(52.08 mL, 550.9 mmol) were added to diethyl acetone dicarboxylate (50mL, 275.5 mmol) and heated to 135° C. After 1 hour, the reaction mixturewas cooled to room temperature and concentrated. The resulting residuewas cooled to 0° C. and methylamine (40% in water) was added withstirring. After the addition of water (200 mL) the reaction mixture wasstirred at room temperature for 16 hours. The reaction mixture wasdiluted with EtOAc (300 mL), and the resulting layers separated. Theaqueous phase was neutralized with 10% HCl solution to produce thedesired product as a white precipitate, which was filtered and washedwith water. The filtrate was extracted with EtOAc, and the combinedorganic extracts dried (MgSO₄), and concentrated to give a white solid.This second crop of product was rinsed with Et₂O and combined with thefirst crop to yield 29 g (54%) desired product after drying.

Step B: Preparation of4-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethylester: Triethyl amine (7.07 mL, 50.7 mmol) was added to a suspension of4-hydroxy-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethylester (10.0 g, 50.7 mmol) and POCl₃ (27.85 mL, 304.3 mmol). Afterstirring 16 hours, the reaction mixture was concentrated under reducedpressure. The resulting residue was poured onto ice, carefullyneutralized with saturated K₂CO₃ solution, and diluted with EtOAc. Thelayers were separated and the aqueous phase further extracted withEtOAc. The combined organic extracts were dried (MgSO₄) and concentratedunder reduced pressure to yield 7.3 g (67%) clean desired product.

Step C: Preparation of4-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid: To asolution of 4-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid ethyl ester (0.925 g, 4.29 mmol) in a 4:1 mixture of THF:MeOH (20mL) was added a 1 M solution of LiOH (8.6 mL). After stirring for 30minutes, the reaction mixture was acidified to pH 1 with 10% HCl andextracted with EtOAc. The combined organic extracts were washed withbrine, dried (MgSO₄) and concentrated under reduced pressure to give0.732 g (91%) clean desired product.

Step D: Preparation of4-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid: To a solution of i-Pr₂NH (0.39 mL, 2.80 mmol) in THF (4 mL) at 0°C. was added n-BuLi (1.1 mL, 2.80 mmol, 2.5 M solution in hexanes).After stirring 15 minutes, the mixture was cooled to −78° C.4-Bromo-2-fluorophenylamine (0.38 g, 2.0 mmol) was added. After vigorousstirring for 10 minutes, a mixture of the4-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (0.15 g,0.80 mmol) in THF (5 mL) was added. The dry-ice bath was removed after30 minutes, and the reaction mixture was stirred for 17 hours at roomtemperature. The reaction mixture was treated with a 10% aqueous HClsolution (15 mL), extracted with EtOAc, dried (MgSO₄), and concentrated.Trituration with methylene chloride gave 0.21 g (77%) desired product.MS APCI (−) m/z 339, 341 (M−, Br pattern) detected; ¹H NMR (400 mHz,DMSO-d₆) δ 9.61 (s, 1H), 8.53 (s, 1H), 7.69 (dd, 1H), 7.46 (m, 2H), 3.41(s, 3H).

In the foregoing examples a variety of anilines can be used in replaceof 4-bromo-2-fluorophenylamine in Step D of Example 1.

Example 2

4-(4-Bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Cyclopropylmethoxy-amide

Preparation of4-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid cyclopropylmethoxy-amide: A mixture of4-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (0.078 g, 0.229 mmol), EDCI (0.13 g, 0.69 mmol), and HOBt (0.093 g,0.69 mmol) in DMF (5 mL) was stirred for 30 minutes.O-Cyclopropylmethyl-hydroxylamine (0.060 g, 0.69 mmol) was addedfollowed by Et₃N (0.096 mL, 0.69 mmol). After 1 hour, the reactionmixture was diluted with EtOAc and washed with saturated NH₄Cl solution,saturated NaHCO₃ solution and brine. The organic layer was dried (MgSO₄)and concentrated to yield 83 mg (89%) clean desired product. MS APCI (+)m/z 410, 412 (M+, Br pattern) detected; ¹H NMR (400 mHz, DMSO-d₆) δ11.57 (s, 1H), 9.42 (s, 1H), 8.10 (s, 1H), 7.67 (d, 1H), 7.43 (m, 2H),3.70 (d, 2H), 3.35 (s, 3H), 1.11 (m, 1H), 0.54 (m, 2H), 0.27 (m, 2H).

Any of the hydroxylamines used in the foregoing examples can be coupledas described in Example 2. In some instances, a final deprotection stepmay be required. These deprotections can be accomplished by standardliterature methods. Example 3 is one such example in which a finaldeprotection step is required.

Example 3

4-(4-Bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid (2-hydroxyethoxy)-amide

Step A: Preparation of4-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-vinyloxyethoxy)-amide: A mixture of4-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (0.120 g, 0.352 mmol), EDCI (0.10 g, 0.53 mmol), and HOBt (0.071 g,0.53 mmol) in DMF (5 mL) was stirred for 3 hours.O-(2-Vinyloxy-ethyl)-hydroxylamine (0.071 mL, 0.70 mmol) was addedfollowed by Et₃N (0.098 mL, 0.70 mmol). After 2 hours, the reactionmixture was diluted with EtOAc and washed with saturated NH₄Cl solution,saturated NaHCO₃ solution and brine. The organic layer was dried (MgSO4)and concentrated under reduced pressure. Purification by flash columnchromatography (3% MeOH in methylene chloride) gave 0.078 g (52%) cleandesired product.

Step B: Preparation of4-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-hydroxyethoxy)-amide: 1 N HCl solution (0.36 mL) was added to astirred solution of4-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-vinyloxyethoxy)-amide (0.077 g, 0.181 mmol) in a 1:1 mixture ofEtOH:THF (6 mL). After 1 hour, the pH of the reaction mixture wasadjusted to 5 to 7 with 2 N NaOH solution. The reaction mixture wasdiluted with EtOAc, washed with water, dried (MgSO₄) and concentrated.Trituration with diethyl ether yielded 55 mg (76%) clean desired productas a white solid. MS APCI (−) m/z 398, 400 (M−, Br pattern) detected; ¹HNMR (400 mHz, DMSO-d₆) δ 11.65 (s, 1H), 9.41 (s, 1H), 8.13 (s, 1H), 7.68(d, 1H), 7.43 (m, 3H), 4.74 (t, 1H), 3.91 (t, 2H), 3.62 (m, 2H), 3.36(s, 3H).

Example 4

4-(4-Bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Amide

Preparation of4-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid amide: A mixture of4-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (0.069 g, 0.202 mmol), EDCI (0.12 g, 0.61 mmol), and HOBt (0.082 g,0.61 mmol) in DMF (5 mL) was stirred for 30 minutes. NH₄Cl (0.033 g,0.61 mmol) was added followed by Et₃N (0.085 mL, 0.61 mmol). After 1hour, the reaction mixture was diluted with EtOAc and washed withsaturated NH₄Cl solution, saturated NaHCO₃ solution and brine. Theorganic layer was dried (MgSO₄) and concentrated to yield 52 mg (76%)clean desired product as an off-white solid. MS APCI (+) m/z 340, 342(M+, Br pattern) detected; ¹H NMR (400 mHz, DMSO-d₆) δ 10.39 (s, 1H),8.34 (s, 1H), 7.67 (dd, 1H), 7.43 (m, 2H), 3.36 (s, 3H).

The following compounds were prepared as described in Examples 1, 2 and3 using benzyl amine in place of methylamine in Step A of Example 1 andno Et₃N in Step B of Example 1.

Example 5

1-Benzyl-4-(4-bromo-2-fluorophenylamino)-6-oxo-1,6-dihydropyridine-3-carboxylicAcid

MS APCI (−) m/z 415, 417 (M−, Br pattern) detected; ¹H NMR (400 mHz,DMSO-d₆) δ 9.62 (s, 1H), 8.60 (s, 1H), 7.65 (dd, 1H), 7.48 (m, 2H), 7.32(m, 5H), 5.49 (s, 1H), 5.12 (s, 2H).

Example 6

1-Benzyl-4-(4-bromo-2-fluorophenylamino)-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Cyclopropylmethoxy Amide

MS APCI (−) m/z 484, 486 (M−, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 8.04 (s, 1H), 7.49 (d, 1H), 7.40 (m, 2H), 7.32 (m, 6H), 5.12(s, 2H), 3.75 (d, 2H), 1.14 (m, 1H), 0.57 (m, 2H), 0.28 (m, 2H).

Example 7

1-Benzyl-4-(4-bromo-2-fluorophenylamino)-6-oxo-1,6-dihydropyridine-3-carboxylicAcid (2-hydroxyethoxy) Amide

MS APCI (−) m/z 474, 476 (M−, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 8.10 (s, 1H), 7.49 (d, 1H), 7.40 (m, 2H), 7.33 (m, 6H), 5.12(s, 2H), 4.03 (t, 2H), 3.77 (t, 2H).

The following compounds were prepared as previously described with theaddition of a chlorination step. An example of such a chlorination isdescribed below.

A mixture of 4-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid ethyl ester (1.00 g, 4.64 mmol) and NCS (0.68 g, 5.10 mmol) in DMF(30 mL) was stirred for 1 hour. The reaction mixture was diluted withEtOAc and washed with 0.1 N HCl solution. The organic layer was dried(MgSO₄) and concentrated under reduced pressure to give 1.10 g (95%) of4,5-dichloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethylester.

Example 8

4-(4-Bromo-2-fluorophenylamino)-5-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Cyclopropylmethoxy Amide

MS APCI (+) m/z 444, 446 (M+, Cl, Br pattern) detected; ¹H NMR (400 mHz,DMSO-d₆) δ 11.52 (s, 1H), 8.78 (s, 1H), 7.98 (s, 1H), 7.52 (dd, 1H),7.29 (dd, 1H), 6.93 (t, 1H), 3.47 (s, 3H), 3.40 (d, 2H), 1.01 (m, 1H),0.50 (m, 2H), 0.20 (m, 2H).

Example 9

4-(4-Bromo-2-fluorophenylamino)-5-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Amide

MS APCI (+) m/z 374, 376 (M+, Cl, Br pattern) detected; ¹H NMR (400 mHz,DMSO-d₆) δ 10.16 (s, 1H), 8.33 (s, 1H), 7.99 (br. s, 1H), 7.64 (br. s,1H), 7.55 (dd, 1H), 7.30 (dd, 1H), 6.90 (m, 1H), 3.48 (s, 3H).

Example 10

4-(4-Bromo-2-fluorophenylamino)-5-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid (2-hydroxyethoxy)-amide

MS APCI (+) m/z 434, 436 (M+, Cl, Br pattern) detected; ¹H NMR (400 mHz,DMSO-d₆) δ 11.60 (s, 1H), 8.82 (s, 1H), 8.03 (s, 1H), 7.52 (dd, 1H),7.28 (d, 1H), 6.92 (t, 1H), 4.69 (t, 1H), 3.68 (m, 2H), 3.52 (m, 2H),3.47 (s, 3H).

Example 11

4-(4-Bromo-2-fluorophenylamino)-5-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid

MS APCI (+) m/z 375, 377 (M+, Cl, Br pattern) detected; ¹H NMR (400 mHz,DMSO) δ 9.58 (s, 1H), 8.58 (s, 1H), 7.57 (dd, 1H), 7.33 (d, 1H), 7.0 (t,1H), 3.53 (s, 3H).

Example 12

4-(4-Bromo-2-fluorophenylamino)-5-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Ethoxy-amide

MS APCI (+) m/z 418, 420 (M+, Cl, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.85 (s, 1H), 7.34 (dd, 1H), 7.26 (dd, 1H), 6.97 (t, 1H), 3.69(q, 2H), 3.58 (s, 3H), 1.20 (t, 3H).

Example 13

1-Benzyl-4-(4-bromo-2-fluorophenylamino)-5-chloro-6-oxo-1,6-dihydropyridine-3-carboxylicAcid

MS APCI (−) m/z 449, 451 (M−, Cl, Br pattern) detected; ¹H NMR (400 mHz,DMSO-d₆) δ 9.66 (s, 1H), 8.67 (s, 1H), 7.56 (d, 1H), 7.34 (m, 6H), 7.03(t, 1H), 5.23 (s, 2H).

Example 14

1-Benzyl-4-(4-bromo-2-fluorophenylamino)-5-chloro-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Amide

MS APCI (−) m/z 448, 450 (M−, Cl, Br pattern) detected; ¹H NMR (400 mHz,DMSO-D₆) δ 10.21 (s, 1H), 8.45 (s, 1H), 8.07 (br. s, 1H), 7.65 (br. s,1H), 7.53 (dd, 1H), 7.33 (m, 6H), 6.94 (t, 1H), 5.12 (s, 2H).

Example 15

1-Benzyl-4-(4-bromo-2-fluorophenylamino)-5-chloro-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Cyclopropylmethoxy-amide

MS APCI (−) m/z 518, 520 (M−, Cl, Br pattern) detected; ¹H NMR (400 mHz,DMSO-d₆) δ 8076 (s, 1H), 8.08 (s, 1H), 7.51 (d, 1H), 7.35 (m, 6H), 6.96(t, 1H), 5.11 (s, 2H), 3.36 (d, 2H), 0.99 (m, 1H), 0.49 (m, 2H), 0.19(m, 2H).

Example 16

1-Benzyl-4-(4-bromo-2-fluorophenylamino)-5-chloro-6-oxo-1,6-dihydropyridine-3-carboxylicAcid (2-hydroxyethoxy)-amide

MS APCI (−) m/z 508, 510 (M−, Cl, Br pattern) detected; ¹H NMR (400 mHz,DMSO-d₆) δ 8.80 (s, 1H), 8.13 (s, 1H), 7.51 (dd, 1H), 7.35 (m, 6H), 7.27(d, 1H), 6.95 (t, 1H), 5.12 (s, 2H), 4.67 (t, 1H), 3.65 (m, 2H), 3.51(m, 2H).

The following compounds were prepared as previously described with theaddition of a fluorination step. An example of such a fluorination isdescribed below.

A mixture of 4-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid ethyl ester (1.00 g, 4.64 mmol), LiOH (0.22 g, 9.30 mmol) and[1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane-bis(tetrafluoroborate)(3.30 g, 9.30 mmol) in MeCN (50 mL) was stirred at 85° C. for 1 hour.The reaction was cooled to room temperature and concentrated underreduced pressure. The residue was dissolved in water and extracted withEtOAc. The combined organic extracts were dried (MgSO₄) and concentratedunder reduced pressure. Flash column chromatography (60:40hexanes:EtOAc) removed starting material. The partially purified ethylester was then hydrolyzed by dissolving in 4:1 THF:MeOH (10 mL) followedby treatment with 1 M LiOH solution (2.8 mL). After 1 hour, the reactionmixture was acidified to pH 1 with 10% HCl solution and extracted withEtOAc. The combined organic extracts were washed with brine, dried(MgSO₄) and concentrated to yield 0.25 g (26% for two steps)4-chloro-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid,which could be further purified by trituration with diethyl ether.

Example 17

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Cyclopropylmethoxy-amide

MS APCI (+) m/z 428, 430 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.85 (s, 1H), 7.36 (dd, 1H), 7.28 (d, 1H), 7.01 (m, 1H), 3.69(d, 2H), 3.57 (s, 3H), 0.89 (m, 1H), 0.58 (m, 2H), 0.30 (m, 2H).

Example 18

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid (2-hydroxyethoxy)-amide

MS APCI (+) m/z 418, 420 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.90 (s, 1H), 7.36 (dd, 1H), 7.28 (dd, 1H), 7.01 (m, 1H), 3.98(m, 2H), 3.75 (m, 2H), 3.58 (s, 3H).

Example 19

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid

MS APCI (−) m/z 357, 359 (M−1, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 8.33 (s, 1H), 7.30 (d, 1H), 7.26 (d, 1H), 7.03 (td, 1H), 3.62(s, 3H).

Example 20

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Amide

MS (+) m/z 358, 360 (M+, Br pattern) detected; ¹H NMR (400 mHz, CD₃OD) δ8.11 (s, 1H), 7.36 (dd, 1H), 7.28 (dd, 1H), 7.02 (m, 1H), 3.58 (s, 3H).

Example 21

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Ethoxy-amide

MS APCI (+) m/z 402, 404 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.87 (s, 1H), 7.35 (dd, 1H), 7.27 (d, 1H), 7.01 (td, 1H), 3.94(q, 2H), 3.58 (s, 3H), 1.27 (t, 3H).

Example 22

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Methoxy-amide

MS APCI (+) m/z 388, 390 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.87 (s, 1H), 7.35 (dd, 1H), 7.27 (d, 1H), 7.01 (td, 1H), 3.75(s, 3H), 3.58 (s, 3H).

Example 23

4-(4-Chloro-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Cyclopropylmethoxy-amide

MS APCI (+) m/z 384, 386 (M+, Cl pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.56 (s, 1H), 6.93 (dd, 1H), 6.85 (d, 1H), 6.79 (td, 1H), 3.41(d, 2H), 3.28 (s, 3H), 0.87 (m, 1H), 0.29 (q, 2H), 0.01 (q, 2H).

Example 24

4-(4-Chloro-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Ethoxy-amide

MS APCI (+) m/z 358, 360 (M+, Cl pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.88 (s, 1H), 7.22 (d, 1H), 7.14 (d, 1H), 7.08 (td, 1H), 3.95(q, 2H), 3.58 (s, 3H), 1.28 (t, 3H).

Example 25

4-(4-Chloro-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Amide

MS APCI (+) m/z 314, 316 (M+, Cl pattern) detected; ¹H NMR (400 mHz,DMSO) δ 9.96 (s, 1H), 8.23 (s, 1H), 7.99 (bs, 1H), 7.64 (bs, 1H), 7.45(dd, 1H), 7.21 (d, 1H), 7.09 (td, 1H), 3.46 (s, 3H).

Example 26

5-Fluoro-4-(2-fluoro-4-methylphenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Cyclopropylmethoxy-amide

MS APCI (+) m/z 364 (M+1) detected; ¹H NMR (400 mHz, CD₃OD) δ 7.82 (s,1H), 7.0 (td, 1H), 6.94 (d, 1H), 6.93 (s, 1H), 3.69 (d, 2H), 3.56 (s,3H), 2.32 (s, 3H), 1.16 (m, 1H), 0.58 (q, 2H), 0.30 (q, 2H).

Example 27

5-Fluoro-4-(2-fluoro-4-methylphenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Ethoxy-amide

MS APCI (+) m/z 338 (M+1) detected; ¹H NMR (400 mHz, CD₃OD) δ 7.85 (s,1H), 7.0 (td, 1H), 6.94 (d, 1H), 6.93 (s, 1H), 3.93 (q, 2H), 3.56 (s,3H), 2.32 (s, 3H), 1.27 (t, 3H).

Example 28

4-(4-Bromo-2-methylphenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Ethoxy-amide

MS APCI (+) m/z 398, 400 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.84 (s, 1H), 7.35 (s, 1H), 7.25 (dd, 1H), 6.85 (dd, 1H), 3.92(q, 2H), 3.57 (s, 3H), 2.30 (s, 3H), 1.28 (t, 3H).

Example 29

4-(4-Bromo-2-methylphenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Cyclopropylmethoxy-amide

MS APCI (+) m/z 424, 426 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.82 (s, 1H), 7.35 (s, 1H), 7.25 (dd, 1H), 6.85 (dd, 1H), 3.67(d, 2H), 3.57 (s, 3H), 2.29 (s, 3H), 1.16 (m, 1H), 0.59 (q, 2H), 0.31(q, 2H).

Example 30

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Tert-butoxy-amide

MS APCI (+) m/z 430, 432 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.94 (s, 1H), 7.36 (dd, 1H), 7.28 (d, 1H), 7.01 (td, 1H), 3.60(s, 3H), 1.30 (s, 9H).

Example 31

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Cyclopropylmethyl-amide

MS APCI (+) m/z 412, 414 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.97 (s, 1H), 7.32 (dd, 1H), 7.25 (d, 1H), 6.98 (td, 1H), 3.60(s, 3H), 3.15 (d, 2H), 1.04 (m, 1H), 0.54 (q, 2H), 0.26 (q, 2H).

Example 32

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Methylamide

MS APCI (+) m/z 372, 374 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.93 (s, 1H), 7.35 (dd, 1H), 7.27 (d, 1H), 7.0 (td, 1H), 3.57(s, 3H), 2.83 (s, 3H).

Example 33

5-Fluoro-4-(2-fluoro-4-methylsulfanyl-phenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Ethoxy-amide

Prepared as described previously using2-fluoro-4-methylsulfanyl-phenylamine, which was prepared according toWO 03/062191.

MS APCI (+) m/z 370 (M+1) detected; ¹H NMR (400 mHz, CD₃OD) δ 7.83 (s,1H), 7.03 (m, 3H), 3.96 (q, 2H), 3.58 (s, 3H), 2.48 (s, 3H), 1.29 (t,3H).

Example 34

5-Fluoro-4-(2-fluoro-4-methylsulfanyl-phenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Methoxy-amide

MS APCI (+) m/z 370 (M+1) detected; ¹H NMR (400 mHz, CD₃OD) δ 7.83 (s,1H), 7.03 (m, 3H), 3.96 (q, 2H), 3.58 (s, 3H), 2.48 (s, 3H), 1.29 (t,3H).

Example 35

5-Fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Ethoxy-amide

MS APCI (+) m/z 450 (M+1) detected; ¹H NMR (400 mHz, CD₃OD) δ 7.86 (s,1H), 7.48 (dd, 1H), 7.44 (d, 1H), 6.84 (td, 1H), 3.95 (q, 2H), 3.58 (s,3H), 1.28 (t, 3H).

Example 36

5-Fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Methoxy-amide

MS APCI (+) m/z 436 (M+1) detected; ¹H NMR (400 mHz, CD₃OD) δ 7.84 (s,1H), 7.47 (dd, 1H), 7.44 (d, 1H), 6.83 (td, 1H), 3.77 (s, 3H), 3.59 (s,3H).

Example 37

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Hydroxyamide

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid hydroxyamide was prepared from4-(4-bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid tert-butoxy-amide by TFA mediated deprotection.4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid tert-butoxy-amide (35 mg, 0.081 mmol) was treated with TFA (0.63mL). After 4 days stirring, the reaction mixture was concentrated underreduced pressure. Purification by flash column chromatography (10% MeOHin methylene chloride) followed by saturated NaHCO₃ solution wash of anethyl acetate solution of the product gave clean desired product (10 mg,33%); MS APCI (+) m/z 356, 358 (M—OH, Br pattern) detected; ¹H NMR (400mHz, CD₃OD) δ 7.84 (s, 1H), 7.35 (dd, 1H), 7.28 (d, 1H), 7.01 (td, 1H),3.57 (s, 3H).

Example 38

4-(4-Bromo-2-fluorophenylamino)-1-cyclopropylmethyl-5-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid

MS APCI (−) m/z 393, 395 (M−, Br pattern) detected; ¹H NMR (400 MHz,DMSO-d₆) δ 9.12 (s, 1H), 8.51 (s, 1H), 7.56 (d, 1H), 7.28 (d, 1H), 6.69(t, 1H), 3.84 (d, 2H), 1.61 (s, 3H), 1.25 (m, 1H), 0.50 (q, 2H), 0.39(q, 2H).

Example 39

4-(4-Bromo-2-fluorophenylamino)-1-cyclopropylmethyl-5-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Amide

MS APCI (−) m/z 392, 394 (M−, Br pattern) detected; ¹H NMR (400 MHz,CD₃OD) δ 8.14 (s, 1H), 7.33 (d, 1H), 7.21 (d, 1H), 6.63 (t, 1H), 3.87(d, 2H), 1.76 (s, 3H), 1.35 (m, 1H), 0.60 (q, 2H), 0.46 (q, 2H).

Example 40

4-(4-Bromo-2-fluorophenylamino)-1-cyclopropylmethyl-5-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid (2-hydroxy-1,1-dimethylethoxy)-amide

MS APCI (−) m/z 480, 482 (M−, Br pattern) detected; ¹H NMR (400 MHz,DMSO-d₆) δ 11.06 (s, 1H), 8.36 (s, 1H), 8.02 (s, 1H), 7.50 (d, 1H), 7.22(d, 1H), 6.57 (t, 1H), 4.60 (t, 1H), 3.78 (d, 2H), 3.16 (m, 2H), 1.71(s, 3H), 1.29 (m, 1H), 1.11 (s, 6H), 0.51 (q, 2H), 0.43 (q, 2H).

Example 41

(S)-4-(4-Bromo-2-fluorophenylamino)-1-cyclopropylmethyl-5-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid (2-hydroxy-propoxy)-amide

MS APCI (−) m/z 466, 468 (M−, Br pattern) detected; ¹H NMR (400 MHz,CD₃OD) δ 7.93 (s, 1H), 7.34 (dd, 1H), 7.20 (d, 1H), 6.66 (t, 1H), 3.88(m, 1H), 3.86 (d, 2H), 3.71 (dd, 1H), 3.59 (dd, 1H), 1.86 (s, 3H), 1.33(m, 1H), 1.12 (d, 3H), 0.91 (q, 2H), 0.46 (q, 2H).

Example 42

4-(4-Bromo-2-chlorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid

MS APCI (−) m/z 373, 375 (M−, Cl, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 8.43 (s, 1H), 7.62 (s, 1H), 7.42 (dd, 1H), 7.01 (m, 1H), 3.61(s, 3H).

Example 43

4-(4-Bromo-2-chlorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid cyclopropylmethoxy-amide

MS APCI (+) m/z 444, 446 (M+, Cl, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.89 (s, 1H), 7.60 (d, 1H), 7.39 (dd, 1H), 6.92 (dd, 1H), 3.73(d, 2H), 3.59 (s, 3H), 1.17 (m, 1H), 0.58 (m, 2H), 0.30 (m, 2H).

Example 44

4-(4-Bromo-2-chlorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Amide

MS APCI (+) m/z 374, 376 (M+, Cl, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 8.13 (s, 1H), 7.59 (d, 1H), 7.39 (dd, 1H), 6.92 (dd, 1H), 3.60(s, 3H).

Example 45

4-(4-Bromo-2-chlorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid (2-hydroxyethoxy)-amide

MS APCI (+) m/z 434, 436 (M+, Cl, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.94 (s, 1H), 7.60 (d, 1H), 7.40 (dd, 1H), 6.92 (dd, 1H), 4.01(m, 2H), 3.76 (m, 2H), 3.59 (s, 3H).

Example 46

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid (2-hydroxy-1,1-dimethylethoxy)-amide

MS APCI (+) m/z 446, 448 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.94 (s, 1H), 7.36 (d, 1H), 7.28 (d, 1H), 7.02 (td, 1H), 3.59(s, 3H), 3.41 (s, 2H), 1.27 (s, 6H).

Example 47

(S)-4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid (2-hydroxy-propoxy)-amide

MS APCI (+) m/z 432, 434 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.89 (s, 1H), 7.36 (d, 1H), 7.28 (d, 1H), 7.02 (td, 1H), 3.99(m, 1H), 3.83 (dd, 1H), 3.72 (dd, 1H), 3.58 (s, 3H), 1.16 (d, 3H).

The following compounds were prepared as previously described by usingthe appropriate amine in place of methylamine in Step A of Example 1.

Example 48

4-(4-Bromo-2-fluorophenylamino)-1-cyclopropyl-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicAcid

MS APCI (+) m/z 385, 387 (M+, Br pattern) detected; ¹H NMR (400 mHz,DMSO-D₆) δ 9.29 (s, 1H), 8.08 (s, 1H), 7.58 (dd, 1H), 7.36 (d, 1H), 7.12(m, 1H), 3.35 (m, 1H), 1.02 (m, 2H), 0.90 (m, 2H).

Example 49

4-(4-Bromo-2-fluorophenylamino)-1-cyclopropyl-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicAcid cyclopropylmethoxy-amide

MS APCI (+) m/z 454, 456 (M+, Br pattern) detected; ¹H NMR (400 mHz,DMSO-D₆) δ 11.78 (s, 1H), 9.07 (s, 1H), 7.70 (s, 1H), 7.55 (dd, 1H),7.32 (dd, 1H), 7.03 (m, 1H), 3.66 (d, 2H), 3.35 (m, 1H), 1.07 (m, 1H),0.98 (m, 4H), 0.53 (m, 2H), 0.25 (m, 2H).

Example 50

4-(4-Bromo-2-fluorophenylamino)-1-cyclopropyl-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Amide

MS APCI (+) m/z 384, 386 (M+, Br pattern) detected; ¹H NMR (400 mHz,DMSO-D₆) δ 10.03 (s, 1H), 8.24 (br. s, 1H), 7.95 (s, 1H), 7.63 (br. s,1H), 7.56 (dd, 1H), 7.33 (d, 1H), 7.00 (m, 1H), 3.35 (m, 1H), 0.99 (m,4H).

Example 51

4-(4-Bromo-2-fluorophenylamino)-1-cyclopropyl-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicAcid (2-hydroxyethoxy)-amide

MS APCI (+) m/z 444, 446 (M+, Br pattern) detected; ¹H NMR (400 mHz,DMSO-D₆) δ 11.87 (s, 1H), 9.09 (s, 1H), 7.74 (s, 1H), 7.56 (dd, 1H),7.32 (d, 1H), 7.02 (m, 1H), 3.89 (m, 2H), 3.59 (m, 2H), 3.38 (m, 1H),0.99 (m, 4H).

Example 52

4-(4-Bromo-2-fluorophenylamino)-1-ethyl-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Cyclopropylmethoxy-amide

MS APCI (+) m/z 442, 444 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.85 (s, 1H), 7.36 (dd, 1H), 7.28 (d, 1H), 7.02 (td, 1H), 4.05(q, 2H), 3.70 (d, 2H), 1.36 (t, 3H), 1.17 (m, 1H), 0.58 (q, 2H), 0.31(q, 2H).

Example 53

4-(4-Bromo-2-fluorophenylamino)-1-ethyl-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Amide

MS APCI (+) m/z 372, 374 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 8.10 (s, 1H), 7.35 (dd, 1H), 7.28 (d, 1H), 7.02 (td, 1H), 4.05(q, 2H), 1.37 (t, 3H).

Example 54

4-(4-Bromo-2-fluorophenylamino)-1-ethyl-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicAcid (2-hydroxy-1,1-dimethylethoxy)-amide

MS APCI (+) m/z 460, 462 (M+, Br pattern) detected; ¹H NMR (400 mHz,DMSO) δ 11.20 (bs, 1H), 8.80 (bs, 1H), 8.01 (s, 1H), 7.55 (d, 1H), 7.32(d, 1H), 7.03 (td, 1H), 4.40 (q, 2H), 3.28 (s, 2H), 1.27 (t, 3H), 1.17(s, 6H).

Example 55

4-(4-Bromo-2-fluorophenylamino)-1-ethyl-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicAcid (2-methoxy-ethoxy)-amide

MS APCI (+) m/z 446, 448 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.88 (s, 1H), 7.36 (dd, 1H), 7.28 (d, 1H), 7.02 (td, 1H), 4.05(m, 4H), 3.64 (m, 2H), 3.37 (s, 3H), 1.37 (t, 3H).

Example 56

4-(4-Bromo-2-fluorophenylamino)-1-ethyl-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Methoxy-amide

MS APCI (+) m/z 402, 404 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.87 (s, 1H), 7.36 (d, 1H), 7.29 (d, 1H), 7.02 (td, 1H), 4.02(q, 2H), 3.75 (s, 3H), 1.36 (t, 3H).

Example 57

4-(4-Bromo-2-fluorophenylamino)-1-ethyl-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Methylamide

MS APCI (+) m/z 386, 388 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.93 (s, 1H), 7.35 (dd, 1H), 7.27 (d, 1H), 7.0 (td, 1H), 4.04(q, 2H), 2.83 (s, 3H), 1.37 (t, 3H).

Example 58

4-(4-Bromo-2-fluorophenylamino)-1-ethyl-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicAcid

MS APCI (−) m/z 371, 373 (M−, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 8.41 (s, 1H), 7.38 (d, 1H), 7.30 (d, 1H), 7.10 (td, 1H), 4.08(q, 2H), 1.36 (t, 3H).

Example 59

4-(4-Bromo-2-fluorophenylamino)-1-ethyl-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicAcid (2-hydroxyethoxy)-amide

MS APCI (+) m/z 432, 434 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.90 (s, 1H), 7.36 (dd, 1H), 7.28 (d, 1H), 7.02 (td, 1H), 4.05(q, 2H), 3.99 (t, 2H), 3.75 (t, 2H), 1.37 (t, 3H).

Example 60

(R)-4-(4-Bromo-2-fluorophenylamino)-1-ethyl-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicAcid (2-hydroxy-propoxy)-amide

MS APCI (+) m/z 446, 448 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.90 (s, 1H), 7.36 (dd, 1H), 7.28 (d, 1H), 7.02 (td, 1H), 4.05(q, 2H), 3.99 (m, 1H), 3.83 (dd, 1H), 3.73 (dd, 1H), 1.36 (t, 3H), 1.16(d, 3H).

Example 61

(S)-4-(4-Bromo-2-fluorophenylamino)-1-ethyl-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicAcid (2-hydroxy-propoxy)-amide

MS APCI (+) m/z 446, 448 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.90 (s, 1H), 7.36 (d, 1H), 7.28 (d, 1H), 7.02 (td, 1H), 4.04(q, 2H), 3.99 (m, 1H), 3.83 (dd, 1H), 3.72 (dd, 1H), 1.36 (t, 3H), 1.16(d, 3H).

Example 62

4-(4-Bromo-2-fluorophenylamino)-1-ethyl-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicAcid (2-hydroxybutoxy)-amide

MS APCI (+) m/z 460, 462 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.90 (s, 1H), 7.36 (dd, 1H), 7.28 (d, 1H), 7.02 (td, 1H), 4.05(q, 2H), 3.89 (d, 1H), 3.75 (m, 2H), 1.54 (m, 1H), 1.45 (m, 1H), 1.36(t, 3H), 0.98 (t, 3H).

Example 63

4-(4-Bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid

Preparation of4-hydroxy-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethylester: Triethyl orthoformate (3.85 mL, 23.12 mmol) and acetic anhydride(4.37 mL, 46.25 mmol) were added to 2-methyl-3-oxo-pentanedioic aciddiethyl ester (Caliskan et al Aust. J. Chem. 1999, 52 (11), 1013-1020)(5.0 g, 23.1 mmol) and the reaction mixture heated to 135° C. After 1hour, the reaction mixture was cooled to room temperature andconcentrated under reduced pressure. The residue was cooled to 0° C. andmethylamine (40% in water, 5.0 mL, 57.81 mmol) was added with stirring.Water (20 mL) was added and the reaction mixture stirred for 16 hours.The reaction mixture was extracted with ethyl acetate and the aqueouslayer acidified to pH 2 with 10% aqueous HCl. The acidified aqueouslayer was extracted with ethyl acetate. The combined organic extractswere dried (MgSO₄) and concentrated to give a solid. Trituration withdiethyl ether yielded 4.88 g (55%) clean desired product.4-Hydroxy-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethylester was carried forward as described in Example 1, Steps B-D. MS APCI(−) m/z 353, 355 (M−, Br pattern) detected; ¹H NMR (400 mHz, CD₃OD) δ8.49 (s, 1H), 7.36 (dd, 1H), 7.24 (dd, 1H), 6.71 (m, 1H), 3.60 (s, 3H),1.68 (s, 3H).

The following compounds were prepared as described in Examples 1 (StepsB-D), 2, 3 and 63.

Example 64

4-(4-Bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Cyclopropylmethoxy-amide

MS APCI (+) m/z 424, 426 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.88 (s, 1H), 7.33 (dd, 1H), 7.20 (dd, 1H), 6.65 (m, 1H), 3.59(d, 2H), 3.57 (s, 3H), 1.83 (s, 3H), 1.10 (m, 1H), 0.54 (m, 2H), 0.25(m, 2H).

Example 65

4-(4-Bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Amide

MS APCI (+) m/z 354, 356 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 8.14 (s, 1H), 7.33 (dd, 1H), 7.20 (d, 1H), 6.63 (m, 1H), 3.58(s, 3H), 1.75 (s, 3H).

Example 66

4-(4-Bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid (2-hydroxyethoxy)-amide

MS APCI (+) m/z 414, 416 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.93 (s, 1H), 7.33 (dd, 1H), 7.20 (d, 1H), 6.65 (m, 1H), 3.88(m, 2H), 3.68 (m, 2H), 3.57 (s, 3H), 1.83 (s, 3H).

Example 67

4-(4-Bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid (2-hydroxy-1,1-dimethylethoxy)-amide

MS APCI (+) m/z 442, 444 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.98 (s, 1H), 7.33 (dd, 1H), 7.20 (d, 1H), 6.62 (t, 1H), 3.59(s, 3H), 1.82 (s, 3H), 1.21 (s, 6H).

Example 68

4-(4-Bromo-2-chlorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid (2-hydroxy-1,1-dimethylethoxy)-amide

MS APCI (−) m/z 456, 458 (M−, Cl, Br pattern) detected; ¹H NMR (400 MHz,CD₃OD) δ 8.01 (s, 1H), 7.57 (d, 1H), 7.32 (dd, 1H), 6.52 (d, 1H), 3.60(s, 3H), 3.34 (s, 2H), 1.76 (s, 3H), 1.22 (s, 6H).

Example 69

4-(4-Bromo-2-chlorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid (2-hydroxyethoxy)-amide

MS APCI (−) m/z 428, 430 (M−, Cl, Br pattern) detected; ¹H NMR (400 MHz,CD₃OD) δ 7.98 (s, 1H), 7.57 (d, 1H), 7.32 (dd, 1H), 6.53 (d, 1H), 3.94(t, 2H), 3.71 (t, 2H), 3.58 (s, 3H), 1.76 (s, 3H).

Example 70

4-(4-Bromo-2-methylphenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid

MS APCI (−) m/z 349, 351 (M−, Br pattern) detected; ¹H NMR (400 MHz,DMSO-d₆) δ 9.04 (s, 1H), 8.50 (s, 1H), 7.41 (s, 1H), 7.26 (d, 1H), 6.51(d, 1H), 3.49 (s, 3H), 2.26 (s, 3H), 1.50 (s, 3H).

Example 71

4-(4-Bromo-2-methylphenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid (2-hydroxy-1,1-dimethylethoxy)-amide

MS APCI (−) m/z 436, 438 (M−, Br pattern) detected; ¹H NMR (400 MHz,CD₃OD) δ 7.96 (s, 1H), 7.34 (s, 1H), 7.20 (d, 1H), 6.50 (d, 1H), 3.58(s, 3H), 3.28 (s, 2H), 2.29 (s, 3H), 1.72 (s, 3H), 1.21 (s, 6H).

Example 72

4-(4-Bromo-2-methylphenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Cyclopropylmethoxy-amide

MS APCI (−) m/z 418, 420 (M−, Br pattern) detected; ¹H NMR (400 MHz,CD₃OD) δ 7.86 (s, 1H), 7.34 (d, 1H), 7.20 (dd, 1H), 6.52 (d, 1H), 3.57(d, 2H), 3.56 (s, 3H), 2.29 (s, 3H), 1.74 (s, 3H), 1.10 (m, 1H), 0.54(q, 2H), 0.26 (q, 2H).

Example 73

4-(4-Bromo-2-methylphenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid (2-hydroxyethoxy)-amide

MS APCI (−) m/z 408, 410 (M−, Br pattern) detected; ¹H NMR (400 MHz,CD₃OD) δ 7.91 (s, 1H), 7.34 (d, 1H), 7.20 (dd, 1H), 6.52 (d, 1H), 3.87(t, 2H), 3.68 (t, 2H), 3.56 (s, 3H), 2.30 (s, 3H), 1.74 (s, 3H).

Example 74

4-(4-Bromo-2-chlorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Amide

MS APCI (−) m/z 368, 370 (M−, Cl, Br pattern) detected; ¹H NMR (400 MHz,CD₃OD) δ 8.16 (s, 1H), 7.57 (d, 1H), 7.32 (dd, 1H), 6.53 (d, 1H), 3.59(s, 3H), 1.70 (s, 3H).

Example 75

4-(2,4-Dichlorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid

MS APCI (−) m/z 325, 327 (M−, Cl pattern) detected; ¹H NMR (400 MHz,DMSO-d₆) δ 9.27 (s, 1H), 8.52 (s, 1H), 7.62 (d, 1H), 7.29 (dd, 1H), 6.66(d, 1H), 3.51 (s, 3H), 1.56 (s, 3H).

Example 76

4-(4-Chloro-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid

MS APCI (−) m/z 309, 311 (M−, Cl pattern) detected; ¹H NMR (400 MHz,DMSO-d₆) δ 9.14 (s, 1H), 8.50 (s, 1H), 7.45 (dd, 1H), 7.16 (d, 1H), 6.74(t, 1H), 3.50 (s, 3H), 1.60 (s, 3H).

Example 77

4-(2,4-Dichlorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid (2-hydroxyethoxy)-amide

MS APCI (−) m/z 384, 386 (M−, Cl pattern) detected; ¹H NMR (400 MHz,CD₃OD) δ 7.98 (s, 1H), 7.45 (d, 1H), 7.19 (dd, 1H), 6.60 (d, 1H), 3.94(t, 2H), 3.71 (t, 2H), 3.58 (s, 3H), 1.76 (s, 3H).

Example 78

4-(4-Chloro-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid (2-hydroxyethoxy)-amide

MS APCI (−) m/z 368, 370 (M−, Cl pattern) detected; ¹H NMR (400 MHz,CD₃OD) δ 7.93 (s, 1H), 7.20 (dd, 1H), 7.07 (d, 1H), 6.71 (t, 1H), 3.88(t, 2H), 3.68 (t, 2H), 3.57 (s, 3H), 1.82 (s, 3H).

Example 79

4-(4-Bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Methoxy-amide

MS APCI (−) m/z 382, 384 (M−, Br pattern) detected; ¹H NMR (400 MHz,CD₃OD) δ 7.90 (s, 1H), 7.33 (m, 1H), 7.20 (m, 1H), 6.66 (t, 1H), 3.65(s, 3H), 3.57 (s, 3H), 1.83 (s, 3H).

Example 80

4-(4-Bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Ethoxy-amide

MS APCI (−) m/z 396, 398 (M−, Br pattern) detected; ¹H NMR (400 MHz,CD₃OD) δ 7.90 (s, 1H), 7.33 (dd, 1H), 7.20 (m, 1H), 6.65 (t, 1H), 3.83(q, 2H), 3.57 (s, 3H), 1.83 (s, 3H), 1.22 (t, 3H).

Example 81

4-(4-Chloro-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Cyclopropylmethoxy-amide

MS APCI (−) m/z 378, 380 (M−, Cl pattern) detected; ¹H NMR (400 MHz,CD₃OD) δ 7.88 (s, 1H), 7.20 (d, 1H), 7.07 (d, 1H), 6.72 (t, 1H), 3.58(d, 2H), 3.57 (s, 3H), 1.83 (s, 3H), 1.10 (m, 1H), 0.54 (q, 2H), 0.26(q, 2H).

Example 82

4-(2-Fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid (2-hydroxyethoxy)-amide

MS APCI (−) m/z 460 (M−1) detected; ¹H NMR (400 MHz, CD₃OD) δ 7.92 (s,1H), 7.46 (d, 1H), 7.37 (d, 1H), 6.50 (t, 1H), 3.86 (t, 2H), 3.68 (t,2H), 3.57 (s, 3H), 1.83 (s, 3H).

Example 83

(R)-4-(2-Fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid (2,3-dihydroxypropoxy)-amide

MS APCI (−) m/z 490 (M−1) detected; ¹H NMR (400 MHz, CD₃OD) δ 7.93 (s,1H), 7.47 (d, 1H), 7.37 (d, 1H), 6.50 (t, 1H), 3.90 (m, 1H), 3.80 (m,2H), 3.57 (s, 3H), 3.56 (m, 2H), 1.82 (s, 3H).

Example 84

4-(2,4-Dichlorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid cyclopropylmethoxy-amide

MS APCI (−) m/z 394, 396 (M−, Cl pattern) detected; ¹H NMR (400 MHz,CD₃OD) δ 7.93 (s, 1H), 7.45 (s, 1H), 7.18 (d, 1H), 6.60 (d, 1H), 3.65(d, 2H), 3.58 (s, 3H), 1.75 (s, 3H), 1.12 (m, 1H), 0.53 (q, 2H), 0.25(q, 2H).

Example 85

4-(2,4-Dichlorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Ethoxy-amide

MS APCI (−) m/z 368, 370 (M−, Cl pattern) detected; ¹H NMR (400 MHz,CD₃OD) δ 7.93 (s, 1H), 7.42 (d, 1H), 7.17 (dd, 1H), 6.58 (d, 1H), 3.92(q, 2H), 3.59 (s, 3H), 1.75 (s, 3H), 1.26 (t, 3H).

Example 86

4-(4-Bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid (2-cyano-ethyl)-amide

MS APCI (−) m/z 405, 407 (M−, Br pattern) detected; ¹H NMR (400 MHz,CD₃OD) δ 8.00 (s, 1H), 7.33 (dd, 1H), 7.20 (dd, 1H), 6.65 (t, 1H), 3.59(s, 3H), 3.47 (t, 2H), 2.65 (t, 2H), 1.80 (s, 3H).

Example 87

4-(2-Fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Ethoxy-amide

MS APCI (−) m/z 444 (M−1) detected; ¹H NMR (400 MHz, CD₃OD) δ 7.89 (s,1H), 7.46 (dd, 1H), 7.37 (dd, 1H), 6.50 (t, 1H), 3.82 (q, 2H), 3.57 (s,3H), 1.84 (s, 3H), 1.22 (t, 3H).

Example 88

4-(2-Fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Methoxy-amide

MS APCI (−) m/z 430 (M−1) detected; ¹H NMR (400 MHz, CD₃OD) δ 7.89 (s,1H), 7.47 (dd, 1H), 7.37 (dd, 1H), 6.50 (t, 1H), 3.64 (s, 3H), 3.57 (s,3H), 1.83 (s, 3H).

Example 89

4-(4-Bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Hydroxyamide

4-(4-Bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid hydroxyamide was prepared from4-(4-bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid tert-butoxy-amide by TFA deprotection as described in Example 37.MS APCI (+) m/z 370, 372 (M+, Br pattern) detected; ¹H NMR (400 MHz,CD₃OD) δ 7.88 (s, 1H), 7.32 (dd, 1H), 7.20 (dd, 1H), 6.61 (t, 1H), 3.56(s, 3H), 1.77 (s, 3H).

Example 90

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1-pyridin-3-ylmethyl-1,6-dihydropyridine-3-carboxylicAcid

Step A: Preparation of4-(4-bromo-2-fluorophenylamino)-6-chloro-5-fluoro-nicotinic acid: nBuLi(14.7 mL, 36.7 mmol, 2.5 M solution in hexanes) was added to a stirredsolution of diisopropylamine (5.15 mL, 36.7 mmol) in THF (20 mL) at 0°C. After 20 minutes, the reaction mixture was cooled to −78° C. and asolution of 4-bromo-2-fluorophenylamine (4.65 g, 24.5 mmol) in THF (10mL) was added. After 20 minutes, a solution of4,6-dichloro-5-fluoro-nicotinic acid (Sanchez et al J Heterocylc. Chem.1993, 30 (4), 855-9) (2.57 g, 12.25 mmol) in THF (10 mL) was added.After 10 minutes, the reaction mixture was allowed to warm to roomtemperature and stirred for 1 hour. After quenching the reaction mixturewith 10% HCl (20 mL), it was extracted with ethyl acetate. The combinedorganic extracts were dried (MgSO₄) and concentrated under reducedpressure. Trituration with methylene chloride yielded 3.21 g (72%) ofclean desired product.

Step B: Preparation of4-(4-bromo-2-fluorophenylamino)-6-chloro-5-fluoro-nicotinic acid methylester: A hexanes solution of TMSCH₂N₂ (9.46 mL, 18,9 mmol) was added to4-(4-bromo-2-fluorophenylamino)-6-chloro-5-fluoro-nicotinic acid (4.59g, 12.62 mmol) in a solution of 3:1 THF:MeOH (48 mL) at 0° C. Thereaction mixture was warmed to room temperature and stirred for 1 hour.After quenching with AcOH, the reaction mixture was diluted with ethylacetate and water. The layers were separated and the organic layer waswashed with water, saturated NaHCO₃ solution and brine. The organiclayer was dried (MgSO₄) and concentrated to give 4.40 g (92%) cleandesired product.

Step C: Preparation of4-(4-bromo-2-fluorophenylamino)-5-fluoro-6-methoxy-nicotinic acid methylester: Sodium methoxide (2.20 g, 40.8 mmol) was slowly added to astirred solution of4-(4-bromo-2-fluorophenylamino)-6-chloro-5-fluoro-nicotinic acid methylester in 4:1 MeOH:THF (20 mL) at 0° C. The reaction mixture was warmedto room temperature, stirred for 17 hours and then warmed to 40° C. andstirred for 5 hours. After cooling to room temperature, the reactionmixture was quenched with water and extracted with ethyl acetate. Thecombined organic extracts were dried (MgSO4) and concentrated underreduced pressure. The desired product, contaminated with some startingmaterial, was carried forward without purification.

Step D: Preparation of4-(4-bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicacid methyl ester: Hydrobromic acid (5.82 mL, 51.5 mmol) was added to amixture of 4-(4-bromo-2-fluorophenylamino)-5-fluoro-6-methoxy-nicotinicacid methyl ester (0.64 g, 1.72 mmol) and acetic acid (5.9 mL, 103mmol). The reaction mixture was stirred at 90° C. for 20 minutes andthen cooled to room temperature. After water was added to the mixture, awhite precipitate formed. The white solid was collected by filtered andwashed with water and diethyl ether to yield 0.60 g (97%) clean desiredproduct.

Step E: Preparation of4-(4-bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1-pyridin-3-ylmethyl-1,6-dihydropyridine-3-carboxylicacid: Lithium hydride (14 mg, 1.64 mmol) was added to a stirred solutionof4-(4-bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicacid methyl ester (0.190 g, 0.529 mmol) in DMF (5 mL) at 0° C. Afterstirring for 30 minutes, 3-bromomethyl-pyridine hydrobromide (0.14 g,0.53 mmol) was added. The reaction mixture was warmed to roomtemperature and stirred for 16 hours. After quenching with ice water,the reaction mixture was extracted with ethyl acetate. The combinedorganic extracts were dried (MgSO₄) and concentrated under reducedpressure. Purification by flash column chromatography (1% MeOH inmethylene chloride) yielded4-(4-bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1-pyridin-3-ylmethyl-1,6-dihydropyridine-3-carboxylicacid methyl ester. The methyl ester was dissolved in 4:1 THF:MeOH (5 mL)and 1 M LiOH solution (1.1 mL) was added. After 1 hour, the reactionmixture was acidified to pH 1 with 10% aqueous HCl solution andextracted with ethyl acetate. The combined organic extracts were washedwith brine, dried (MgSO4) and concentrated under reduced pressure.Trituration with diethyl ether gave 0.160 g (69% two step yield) cleandesired product. MS APCI (−) m/z 434, 436 (M−, Br pattern) detected; ¹HNMR (400 mHz, DMSO-d₆) δ 9.40 (bs, 1H), 8.65 (s, 1H), 8.61 (s, 1H), 8.51(d, 1H), 7.74 (d, 1H), 7.58 (d, 1H), 7.39 (m, 1H), 7.34 (s, 1H), 7.16(m, 1H), 0.525 (s, 1H).

Example 91

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1-pyridin-3-ylmethyl-1,6-dihydropyridine-3-carboxylicAcid Cyclopropylmethoxy-amide

Prepared as described in Example 2 from4-(4-bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1-pyridin-3-ylmethyl-1,6-dihydropyridine-3-carboxylicacid. MS APCI (+) m/z 505, 507 (M+, Br pattern) detected; ¹H NMR (400mHz, DMSO) δ 11.75 (bs, 1H), 8.97 (bs, 1H), 8.63 (s, 1H), 8.53 (d, 1H),8.13 (s, 1H), 7.78 (d, 1H), 7.55 (dd, 1H), 7.40 (dd, 1H), 7.31 (d, 1H),7.07 (td, 1H), 5.14 (s, 2H), 3.64 (d, 2H), 1.08 (m, 1H), 0.52 (d, 2H),0.25 (d, 2H).

The following compounds were prepared as described in Examples 1, 2, 3,90 and 91 using the appropriate alkyl halide.

Example 92

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1-pyridin-3-ylmethyl-1,6-dihydropyridine-3-carboxylicAcid Propoxy-amide

MS APCI (+) m/z 493, 495 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 8.62 (s, 1H), 8.51 (d, 1H), 8.03 (s, 1H), 7.88 (d, 1H), 7.44(dd, 1H), 7.36 (dd, 1H), 7.27 (d, 1H), 7.02 (td, 1H), 5.24 (s, 2H), 3.82(t, 2H), 1.68 (m, 2H), 0.97 (t, 3H).

Example 93

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1-pyridin-2-ylmethyl-1,6-dihydropyridine-3-carboxylicAcid

MS APCI (−) m/z 434, 436 (M−, Br pattern) detected; ¹H NMR (400 mHz,DMSO) δ 9.40 (s, 1H), 8.56 (s, 1H), 8.51 (d, 1H), 7.79 (t, 1H), 7.59 (d,1H), 7.34 (m, 3H), 7.15 (m, 1H), 5.29 (s, 2H).

Example 94

4-(4-Bromo-2-fluorophenylamino)-1-cyclopropylmethyl-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicAcid

MS APCI (−) m/z 397, 399 (M−, Br pattern) detected; ¹H NMR (400 mHz,DMSO) δ 9.35 (bs, 1H), 8.46 (s, 1H), 7.59 (d, 1H), 7.36 (d, 1H), 7.13(td, 1H), 3.85 (d, 2H), 1.23 (m, 1H), 0.50 (d, 2H), 0.39 (d, 2H).

Example 95

4-(4-Bromo-2-fluorophenylamino)-1-cyclopropylmethyl-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicAcid (2-hydroxy-1,1-dimethylethoxy)-amide

MS APCI (+) m/z 486, 488 (M+, Br pattern) detected; ¹H NMR (400 mHz,DMSO) δ 8.02 (s, 1H), 7.56 (d, 1H), 7.32 (d, 1H), 7.04 (td, 1H), 3.79(d, 2H), 3.28 (s, 2H), 1.28 (m, 1H), 1.17 (s. 6H), 0.52 (d, 2H), 0.43(d, 2H).

Example 96

4-(4-Bromo-2-fluorophenylamino)-1-cyclopropylmethyl-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Amide

MS APCI (+) m/z 398, 400 (M+, Br pattern) detected; ¹H NMR (400 mHz,DMSO) δ 10.04 (s, 1H), 8.22 (s, 1H), 8.05 (bs, 1H), 7.66 (bs, 1H), 7.56(d, 1H), 7.33 (d, 1H), 7.04 (td, 1H), 3.75 (d, 2H), 1.27 (m, 1H), 0.51(d, 2H), 0.43 (d, 2H).

Example 97

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1-pyridin-2-ylmethyl-1,6-dihydropyridine-3-carboxylicAcid Cyclopropylmethoxy-amide

MS APCI (+) m/z 505, 507 (M+, Br pattern) detected; ¹H NMR (400 mHz,DMSO) δ 11.71 (bs, 1H), 9.04 (bs, 1H), 8.52 (d, 1H), 8.07 (s, 1H), 7.80(t, 1H), 7.56 (d, 1H), 7.31 (m, 3H), 7.07 (td, 1H), 5.21 (s, 2H), 3.63(d, 2H), 1.07 (m, 1H), 0.51 (q, 2H), 0.24 (q, 2H).

Example 98

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1-pyridin-2-ylmethyl-1,6-dihydropyridine-3-carboxylicAcid (2-hydroxy-1,1-dimethylethoxy)-amide

MS APCI (+) m/z 523, 525 (M+, Br pattern) detected; ¹H NMR (400 mHz,DMSO) δ 11.23 (bs, 1H), 8.86 (bs, 1H), 8.53 (d, 1H), 8.18 (s, 1H), 7.80(t, 1H), 7.56 (d, 1H), 7.31 (m, 3H), 7.08 (td, 1H), 5.25 (s, 2H), 3.28(s, 2H), 1.56 (s, 6H).

Example 99

1-Benzyl-4-(4-bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicAcid

MS APCI (+) m/z 433, 435 (M+, Br pattern) detected; ¹H NMR (400 mHz,DMSO-D₆) δ 9.35 (s, 1H), 8.54 (s, 1H), 7.59 (dd, 1H), 7.35 (m, 6H), 7.15(m, 1H), 5.22 (s, 2H).

Example 100

1-Benzyl-4-(4-bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Amide

MS APCI (−) m/z 432, 434 (M−, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.18 (s, 1H), 7.36 (m, 6H), 7.27 (d, 1H), 7.02 (m, 1H), 5.20(s, 2H).

Example 101

1-Benzyl-4-(4-bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Cyclopropylmethoxy-amide

MS APCI (−) m/z 502, 504 (M−, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.89 (s, 1H), 7.34 (m, 7H), 7.27 (d, 1H), 7.02 (m, 1H), 5.19(s, 2H), 3.65 (d, 2H), 1.11 (m, 1H), 0.55 (m, 2H), 0.26 (m, 2H).

Example 102

1-Benzyl-4-(4-bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicAcid (2-hydroxyethoxy)-amide

MS APCI (−) m/z 492, 494 (M−, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.96 (s, 1H), 7.36 (m, 7H), 7.27 (d, 1H), 7.04 (m, 1H), 5.19(s, 2H), 3.96 (t, 2H), 3.73 (t, 2H).

Example 103

1-Benzyl-4-(4-bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicAcid (2-amino-ethoxy)-amide Hydrogen Chloride

1-Benzyl-4-(4-bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-amino-ethoxy)-amide was prepared by deprotecting4(2-{[1-benzyl-4-(4-bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1,6-dihydropyridine-3-carbonyl]-aminooxy}-ethyl)-carbamicacid tert-butyl ester under standard conditions; MS APCI (+) m/z 493,495 (M+, Br pattern) detected; ¹H NMR (400 mHz, CD₃OD) δ 8.03 (s, 1H),7.36 (m, 6H), 7.29 (d, 1H), 7.04 (td, 1H), 5.20 (s, 2H), 4.12 (t, 2H),3.17 (t, 2H).

Example 104

4-(4-Bromo-2-fluorophenylamino)-1-cyclohexylmethyl-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicAcid

MS APCI (−) m/z 439, 441 (M−, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 8.21 (s, 1H), 7.32 (dd, 1H), 7.27 (d, 1H), 7.05 (td, 1H), 3.88(d, 2H), 1.85 (m, 1H), 1.79 (m, 2H), 1.69 (m, 3H), 1.25 (m, 3H), 1.05(q, 2H).

Example 105

4-(4-Bromo-2-fluorophenylamino)-1-cyclohexylmethyl-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicAcid (2-hydroxy-1,1-dimethylethoxy)-amide

MS APCI (+) m/z 528, 530 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.85 (s, 1H), 7.36 (d, 1H), 7.28 (d, 1H), 7.02 (td, 1H), 3.86(d, 2H), 3.42 (s, 2H), 1.88 (m, 1H), 1.76 (m, 2H), 1.67 (m, 3H), 1.29(m, 3H), 1.26 (s, 6H), 1.06 (m, 2H), 0.90 (m, 2H).

Example 106

4-(4-Bromo-2-fluorophenylamino)-1-cyclohexylmethyl-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Cyclopropylmethoxy-amide

MS APCI (+) m/z 510, 512 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.76 (s, 1H), 7.36 (d, 1H), 7.28 (d, 1H), 7.02 (td, 1H), 3.84(d, 2H), 3.69 (d, 2H), 1.86 (m, 1H), 1.75 (m, 2H), 1.66 (m, 2H), 1.26(m, 3H), 1.07 (m, 2H), 0.90 (m, 2H), 0.58 (d, 2H), 0.29 (d, 2H).

Example 107

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-(2-methoxyethyl)-6-oxo-1,6-dihydropyridine-3-carboxylicAcid

MS APCI (−) m/z 401, 403 (M−, Br pattern) detected; ¹H NMR (400 mHz,CD⁻³OD) δ 8.32 (s, 1H), 7.38 (dd, 1H), 7.31 (d, 1H), 7.10 (td, 1H), 4.21(t, 2H), 3.66 (t, 2H), 3.35 (s, 3H).

Example 108

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-(2-methoxyethyl)-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Cyclopropylmethoxy-amide

MS APCI (+) m/z 472, 474 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.79 (s, 1H), 7.36 (dd, 1H), 7.28 (dd, 1H), 7.03 (td, 1H), 4.18(t, 2H), 3.68 (m, 4H), 3.35 (s, 3H), 1.15 (m, 1H), 0.59 (q, 2H), 0.30(q, 2H).

Example 109

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-(2-hydroxyethyl)-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Cyclopropylmethoxy-amide

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-(2-hydroxyethyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid cyclopropylmethoxy-amide was prepared by deprotecting4-(4-bromo-2-fluorophenylamino)-1-[2-(tert-butyl-dimethylsilanyloxy)-ethyl]-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicacid cyclopropylmethoxy-amide under standard conditions. MS APCI (+) m/z458, 460 (M+, Br pattern) detected; ¹H NMR (400 mHz, CD₃OD) δ 7.82 (s,1H), 7.35 (dd, 1H), 7.27 (d, 1H), 7.02 (m, 1H), 4.11 (t, 2H), 3.84 (t,2H), 3.72 (m, 2H), 1.16 (m, 1H), 0.59 (m, 2H), 0.31 (m, 2H).

Example 110

4-(4-Bromo-2-fluorophenylamino)-1-(2-cyclopropylethyl)-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicAcid

MS APCI (−) m/z 411, 413 (M−, Br pattern) detected; ¹H NMR (400 mHz, CD₃OD) δ 8.37 (s, 1H), 7.34 (dd, 1H), 7.27 (d, 1H), 7.04 (td, 1H), 4.10(t, 2H), 1.62 (q, 2H), 0.67 (m, 1H), 0.43 (q, 2H), 0.01 (q, 2H).

Example 111

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-(2-morpholin-4-yl-ethyl)-6-oxo-1,6-dihydropyridine-3-carboxylicAcid

MS ESI (+) m/z 458, 460 (M+, Br pattern) detected; ¹H NMR (400 mHz,DMSO) δ 8.34 (s, 1H), 7.58 (d, 1H), 7.35 (d, 1H), 7.10 (td, 1H), 4.10(t, 2H), 3.56 (m, 4H), 3.17 (m, 2H), 2.62 (m, 2H).

Example 112

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-(1-methyl-1H-imidazol-4-ylmethyl)-6-oxo-1,6-dihydropyridine-3-carboxylicAcid

¹H NMR (400 mHz, DMSO) δ 9.37 (s, 1H), 8.68 (bs, 1H), 8.60 (s, 1H), 7.60(d, 1H), 7.56 (s, 1H), 7.37 (d, 1H), 7.14 (td, 1H), 5.20 (s, 2H), 3.77(s, 3H).

Example 113

4-(4-Bromo-2-fluorophenylamino)-1-(2-cyclopropylethyl)-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Amide

MS APCI (+) m/z 412, 414 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 8.12 (s, 1H), 7.35 (dd, 1H), 7.28 (d, 1H), 7.02 (td, 1H), 4.10(t, 2H), 1.76 (q, 2H), 0.72 (m, 1H), 0.47 (q, 2H), 0.05 (q, 2H).

Example 114

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-(2-morpholin-4-yl-ethyl)-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Cyclopropylmethoxy-amide

MS APCI (+) m/z 527, 529 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.85 (s, 1H), 7.36 (d, 1H), 7.28 (d, 1H), 7.03 (td, 1H), 4.13(t, 2H), 3.68 (m, 6H), 2.71 (t, 2H), 2.55 (m, 4H), 1.17 (m, 1H), 0.59(q, 2H), 0.31 (q, 2H).

Example 115

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-(1-methyl-1H-imidazol-4-ylmethyl)-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Cyclopropylmethoxy-amide

MS APCI (+) m/z 508, 510 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.98 (s, 1H), 7.62 (s, 1H), 7.34 (dd, 1H), 7.26 (dd, 1H), 7.16(s, 1H), 7.0 (td, 1H), 5.04 (s, 2H), 3.72 (d, 2H), 3.70 (s, 3H), 1.18(m, 1H), 0.59 (q, 2H), 0.31 (q, 2H).

Example 116

4-(4-Bromo-2-fluorophenylamino)-1-(2-cyclopropylethyl)-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicAcid (2-hydroxyethoxy)-amide

MS APCI (+) m/z 472, 474 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.90 (s, 1H), 7.36 (d, 1H), 7.28 (d, 1H), 7.02 (td, 1H), 4.09(t, 2H), 3.98 (t, 2H), 3.75 (t, 2H), 1.66 (q, 2H), 0.72 (m, 1H), 0.47(q, 2H), 0.06 (q, 2H).

Example 117

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-(1H-imidazol-4-ylmethyl)-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Cyclopropylmethoxy-amide

MS APCI (+) m/z 494, 496 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.99 (s, 1H), 7.70 (s, 1H), 7.35 (dd, 1H), 7.26 (d, 1H), 7.20(s, 1H), 7.0 (td, 1H), 5.10 (s, 2H), 3.72 (d, 2H), 1.16 (m, 1H), 0.59(q, 2H), 0.31 (q, 2H).

Example 118

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1-pyridin-2-ylmethyl-1,6-dihydropyridine-3-carboxylicAcid (2-hydroxyethoxy)-amide

MS APCI (+) m/z 495, 497 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 8.52 (d, 1H), 8.08 (s, 1H), 7.84 (t, 1H), 7.44 (d, 1H), 7.36(m, 2H), 7.27 (d, 1H), 7.04 (td, 1H), 5.27 (s, 2H), 4.0 (t, 2H), 3.75(t, 2H).

Example 119

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-(6-methylpyridin-2-ylmethyl)-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Cyclopropylmethoxy-amide

MS APCI (+) m/z 519, 521 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 8.03 (s, 1H), 7.70 (t, 1H), 7.36 (d, 1H), 7.28 (d, 1H), 7.21(d, 1H), 7.16 (d, 1H), 7.04 (td, 1H), 5.22 (s, 2H), 3.70 (d, 2H), 2.52(s, 3H), 1.17 (m, 1H), 0.58 (q, 2H), 0.30 (q, 2H).

Example 120

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-(6-methyl-pyridin-2-ylmethyl)-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Methoxy-amide

MS APCI (+) m/z 479, 481 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 8.05 (s, 1H), 7.69 (t, 1H), 7.36 (dd, 1H), 7.28 (d, 1H), 7.21(d, 1H), 7.14 (d, 1H), 7.04 (td, 1H), 5.22 (s, 2H), 3.75 (s, 3H), 2.52(s, 3H).

Example 121

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1-pyridin-3-ylmethyl-1,6-dihydropyridine-3-carboxylicAcid (3-aminopropoxy)-amide Hydrogen Chloride

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1-pyridin-3-ylmethyl-1,6-dihydropyridine-3-carboxylicacid (3-aminopropoxy)-amide was prepared by deprotecting(3-{[4-(4-bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1-pyridin-3-ylmethyl-1,6-dihydropyridine-3-carbonyl]-aminooxy}-propyl)-carbamicacid tert-butyl ester under standard conditions. MS APCI (+) m/z 508,510 (M+, Br pattern) detected; ¹H NMR (400 mHz, DMSO) δ 9.01 (s, 1H),8.92 (m, 2H), 8.61 (d, 1H), 8.29 (s, 1H), 8.12 (m, 1H), 7.81 (m, 2H),7.57 (d, 1H), 7.35 (d, 1H), 7.22 (td, 1H), 5.34 (s, 2H), 3.97 (t, 2H),3.01 (q, 2H), 1.91 (m, 2H).

Example 122

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1-pyrazin-2-ylmethyl-1,6-dihydropyridine-3-carboxylicAcid

MS APCI (−) m/z 435, 437 (M−, Br pattern) detected; ¹H NMR (400 mHz,DMSO) δ 9.42 (bs, 1H), 8.71 (s, 1H), 8.63 (s, 1H), 8.58 (s, 2H), 7.59(dd, 1H), 7.36 (d, 1H), 7.15 (td, 1H), 5.39 (s, 2H).

Example 123

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1-pyrazin-2-ylmethyl-1,6-dihydropyridine-3-carboxylicAcid Cyclopropylmethoxy-amide

MS APCI (+) m/z 506, 508 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 8.72 (s, 1H), 8.57 (s, 1H), 8.55 (s, 1H), 8.05 (s, 1H), 7.36(dd, 1H), 7.28 (d, 1H), 7.04 (td, 1H), 5.33 (s, 2H), 3.70 (d, 2H), 1.56(m, 1H), 0.59 (q, 2H), 0.30 (q, 2H).

Example 124

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1-pyrazin-2-ylmethyl-1,6-dihydropyridine-3-carboxylicAcid Ethoxy-amide

MS APCI (+) m/z 480, 482 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 8.71 (s, 1H), 8.57 (s, 1H), 8.55 (s, 1H), 8.07 (s, 1H), 7.36(dd, 1H), 7.28 (d, 1H), 7.04 (td, 1H), 5.33 (s, 2H), 3.95 (q, 2H), 1.28(t, 3H).

Example 125

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1-pyrazin-2-ylmethyl-1,6-dihydropyridine-3-carboxylicAcid Propoxy-amide

MS APCI (+) m/z 494, 496 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 8.72 (s, 1H), 8.58 (s, 1H), 8.55 (s, 1H), 8.07 (s, 1H), 7.36(dd, 1H), 7.28 (d, 1H), 7.04 (td, 1H), 5.34 (s, 2H), 3.84 (t, 2H), 1.69(m, 2H), 0.98 (t, 3H).

Example 126

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1-pyridazin-3-ylmethyl-1,6-dihydropyridine-3-carboxylicAcid Cyclopropylmethoxy-amide

MS APCI (+) m/z 506, 508 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 9.14 (d, 1H), 8.10 (s, 1H), 7.80 (m, 1H), 7.74 (m, 1H), 7.36(dd, 1H), 7.27 (d, 1H), 7.05 (td, 1H), 5.46 (s, 2H), 3.70 (d, 2H), 1.17(m, 1H), 0.58 (q, 2H), 0.30 (q, 2H).

Example 127

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1-pyrimidin-4-ylmethyl-1,6-dihydropyridine-3-carboxylicAcid Cyclopropylmethoxy-amide

MS APCI (+) m/z 506, 508 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 9.09 (s, 1H), 8.75 (d, 1H), 8.0 (s, 1H), 7.48 (d, 1H), 7.38 (d,1H), 7.29 (d, 1H), 7.07 (td, 1H), 5.30 (s, 2H), 3.69 (d, 2H), 1.16 (m,1H), 0.58 (q, 2H), 0.30 (q, 2H).

Example 128

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-methanesulfonylmethyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Cyclopropylmethoxy-amide

Step A:4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-methylsulfanylmethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid methyl ester was prepared as previously described usingchloromethylsulfanylmethane as the electrophile.

Step B:4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-methanesulfonylmethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid methyl ester was prepared from4-(4-bromo-2-fluorophenylamino)-5-fluoro-1-methylsulfanylmethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid methyl ester as follows. A solution of Oxone® (84 mg, 0.14 mmol) inwater (2 mL) was added dropwise to a stirred solution of4-(4-bromo-2-fluorophenylamino)-5-fluoro-1-methylsulfanylmethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid methyl ester (38 mg, 0.091 mmol) in MeOH (2 mL) at roomtemperature. After 4 days stirring, the reaction mixture was dilutedwith water (20 mL), extracted with ethyl acetate, dried (MgSO₄) andconcentrated under reduced pressure. Purification by flash columnchromatography (0.5% MeOH in methylene chloride) gave clean desiredproduct (25 mg, 61%).

Step C:4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-methanesulfonylmethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid cyclopropylmethoxy-amide was prepared from4-(4-bromo-2-fluorophenylamino)-5-fluoro-1-methanesulfonylmethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid methyl ester as previously described. MS APCI (+) m/z 506, 508 (M+,Br pattern) detected; ¹H NMR (400 mHz, CD₃OD) δ 7.84 (s, 1H), 7.31 (dd,1H), 7.27 (d, 1H), 7.04 (td, 1H), 5.37 (s, 2H), 3.78 (d, 2H), 3.06 (s,3H), 1.21 (m, 1H), 0.63 (q, 2H), 0.33 (q, 2H).

Example 129

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicAcid

A stirred solution of4-(4-bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicacid methyl ester (0.10 g, 0.278 mmol) in 4:1 THF:MeOH (5 mL) wastreated with 1 M LiOH solution (0.75 mL). After 8 hours, the reactionmixture was acidified to pH 1 with 1 N HCl and extracted with ethylacetate. The combined organic extracts were washed with brine, dried(MgSO4) and concentrated under reduced pressure to give 0.095 g (99%) ofdesired product as a white solid. MS APCI (−) m/z 343, 345 (M−, Brpattern) detected; ¹H NMR (400 mHz, DMSO) δ 12.34 (bs, 1H), 9.39 (bs,1H), 7.95 (s, 1H), 7.59 (d, 1H), 7.36 (d, 1H), 7.12 (td, 1H).

Example 130

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Cyclopropylmethoxy-amide

Prepared as described in Example 2 from4-(4-bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicacid. MS APCI (+) m/z 414, 416 (M+, Br pattern) detected; ¹H NMR (400mHz, DMSO) δ 9.15 (bs, 1H), 7.59 (s, 1H), 7.55 (dd, 1H), 7.32 (d, 2H),7.02 (td, 1H), 3.64 (d, 2H), 1.07 (m, 1H), 0.50 (q, 2H), 0.24 (q, 2H).

Example 131

5-(5-Amino-[1,3,4]oxadiazol-2-yl)-4-(4-bromo-2-fluorophenylamino)-3-fluoro-1-methyl-1H-pyridin-2-one

Step A: Preparation of4-(4-bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid hydrazide: A mixture of4-(4-bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (70 mg, 0.195 mmol), EDCI (112 mg, 0.585 mmol), and HOBt (79 mg,0.585 mmol) in DMF (3 mL) was stirred for 30 minutes. Hydrazine (19 mg,0.585 mmol) was added followed by Et₃N (0.082 mL, 0.585 mmol). After 3hours, the reaction mixture was diluted with EtOAc and washed withsaturated NH₄Cl solution, saturated NaHCO₃ solution and brine. Theorganic layer was dried (MgSO₄) and concentrated to yield 64 mg (89%)desired product.

Step B: Preparation of5-(5-amino-[1,3,4]oxadiazol-2-yl)-4-(4-bromo-2-fluorophenylamino)-3-fluoro-1-methyl-1H-pyridin-2-one:Cyanogen bromide (36 mg, 0.31 mmol) was added to a suspension of4-(4-bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid hydrazide (63 mg, 0.169 mmol) in dioxane (2 mL) followed by anaqueous NaHCO₃ (2 mL of a 0.09 M solution) solution. After 17 hours,additional cyanogen bromide (14 mg) was added. After 19 hours, thereaction mixture was diluted with water and extracted with ethylacetate. The combined organic extracts were washed with brine, dried(MgSO₄) and concentrated under reduced pressure. Crystallization(MeOH:THF) followed by trituration (Et₂O:MeOH 5:1) gave clean desiredproduct as a white solid (60 mg, 89%). MS APCI (+) m/z 398, 400 (M+, Brpattern) detected; ¹H NMR (400 mHz, CD₃OD) δ 8.06 (s, 1H), 7.37 (d, 1H),7.31 (d, 1H), 7.10 (td, 1H), 3.64 (s, 3H).

The following compounds were prepared similarly using the appropriatecarboxylic acid.

Example 132

5-(5-Amino-[1,3,4]oxadiazol-2-yl)-4-(4-chloro-2-fluorophenylamino)-3-fluoro-1-methyl-1H-pyridin-2-one

MS APCI (+) m/z 354, 356 (M+, Cl pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 8.06 (s, 1H), 7.23 (d, 1H), 7.16 (s, 2H), 3.64 (s, 3H).

Example 133

5-(5-Amino-[1,3,4]oxadiazol-2-yl)-4-(4-bromo-2-fluorophenylamino)-3-fluoro-1-pyrazin-2-ylmethyl-1H-pyridin-2-one

MS APCI (+) m/z 476, 478 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 8.75 (s, 1H), 8.58 (s, 1H), 8.55 (s, 1H), 8.26 (s, 1H), 7.35(dd, 1H), 7.29 (d, 1H), 7.09 (td, 1H), 5.40 (s, 2H).

Example 134

5-(5-Amino-[1,3,4]oxadiazol-2-yl)-4-(4-bromo-2-fluorophenylamino)-1,3-dimethyl-1H-pyridin-2-one

MS APCI (−) m/z 392, 394 (M−, Br pattern) detected; ¹H NMR (400 MHz,CD₃OD) δ 8.14 (s, 1H), 7.36 (d, 1H), 7.23 (d, 1H), 6.72 (t, 1H), 3.63(s, 3H), 1.78 (s, 3H).

Example 135

5-(5-Amino-[1,3,4]oxadiazol-2-yl)-4-(4-bromo-2-methylphenylamino)-3-fluoro-1-methyl-1H-pyridin-2-one

MS APCI (+) m/z 394, 396 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 8.05 (s, 1H), 7.39 (s, 1H), 7.30 (d, 1H), 6.95 (dd, 1H), 3.62(s, 3H), 2.31 (s, 3H).

Example 136

4-(4-Bromo-2-fluorophenylamino)-1,3-dimethyl-5-(5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-1H-pyridin-2-one

1,1′-Carbonyldiimidazole (275 mg, 1.70 mmol) was added to a stirredsolution of4-(4-bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid hydrazide (728 mg, 1.62 mmol (82% pure material)) in DMF (2 mL).After 1 hour, the reaction mixture was diluted with ethyl acetate andwashed with brine. Some of the product precipitated and was collected byfiltration. The filtrate was diluted with 1 N HCl and the layersseparated. The aqueous layer was extracted with ethyl acetate. Thecombined organic extracts were washed with brine, dried (MgSO4) andconcentrated under reduced pressure. The resulting residue wastriturated with diethyl ether to give the desired product which wascombined with the earlier obtained product. The combined yield of cleandesired product was 482 mg (75%); MS APCI (−) m/z 393, 395 (M−, Brpattern) detected; ¹H NMR (400 MHz, DMSO-d₆) δ 8.22 (s, 1H), 7.88 (s,1H), 7.50 (dd, 1H), 7.21 (d, 1H), 6.59 (t, 1H), 3.52 (s, 3H), 1.76 (s,3H).

Example 137

4-(4-Bromo-2-fluorophenylamino)-5-[5-(2-hydroxyethylamino)-[1,3,4]oxadiazol-2-yl]-1,3-dimethyl-1H-pyridin-2-one

Ethanolamine (0.037 mL, 0.61 mmol) was added to a suspension of4-(4-bromo-2-fluorophenylamino)-1,3-dimethyl-5-(5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-1H-pyridin-2-one(81 mg, 0.20 mmol) in EtOH (2 mL). The reaction mixture was heated to90° C. with stirring for 17 hours. After cooling to room temperature,the reaction mixture was concentrated under reduced pressure andpurified by flash column chromatography (5% MeOH in methylene chlorideincreasing to 20% MeOH in 5% steps) to give the desired intermediateadduct (58 mg, 62%). The intermediate (56 mg, 0.12 mmol) was suspendedin 2:1 methylene chloride:MeCN (4.5 mL) and PPh₃ (98 mg, 0.37 mmol),Et₃N (0.14 mL, 1.0 mmol) and CCl₄ (0.036 mL, 0.37 mmol) were added. Theresulting mixture was heated to 55° C. with stirring for 30 minutes.After cooling to room temperature, the reaction mixture was diluted withethyl acetate and washed with brine. The aqueous layer was extractedwith ethyl acetate. The organic layers were combined, washed with brine,dried (MgSO₄) and concentrated under reduced pressure. Purification byflash column chromatography (ethyl acetate) gave clean desired product(24 mg, 45%); MS APCI (−) m/z 436, 438 (M−, Br pattern) detected; ¹H NMR(400 MHz, CD₃OD) δ 8.14 (s, 1H), 7.36 (dd, 1H), 7.22 (dd, 1H), 6.71 (t,1H), 3.71 (t, 2H), 3.63 (s, 3H), 3.41 (t, 2H), 1.79 (s, 3H).

The following compounds were prepared similarly using the appropriateamine. In some instances a final standard deprotection step wasrequired.

Example 138

4-(4-Bromo-2-fluorophenylamino)-1,3-dimethyl-5-[5-(2-methylaminoethylamino)-oxadiazol-2-yl]-1H-pyridin-2-one

MS APCI (−) m/z 449, 451 (M−, Br pattern) detected; ¹H NMR (400 MHz,CD₃OD) δ 8.18 (s, 1H), 7.37 (dd, 1H), 7.23 (d, 1H), 6.71 (t, 1H), 3.66(t, 2H), 3.64 (s, 3H), 3.29 (t, 2H), 2.75 (s, 3H), 1.80 (s, 3H).

Example 139

5-[5-(2-Amino-ethylamino)-[1,3,4]oxadiazol-2-yl]-4-(4-bromo-2-fluorophenylamino)-1,3-dimethyl-1H-pyridin-2-one

MS APCI (+) m/z 437, 439 (M+, Br pattern) detected; ¹H NMR (400 MHz,CD₃OD) δ 8.20 (s, 1H), 7.37 (dd, 1H), 7.23 (dd, 1H), 6.71 (t, 1H), 3.65(s, 3H), 3.63 (t, 2H), 3.22 (t, 2H), 1.80 (s, 3H).

Example 140

4-(4-Bromo-2-fluorophenylamino)-3-fluoro-5-[5-(2-hydroxyethylamino)-[1,3, 4]oxadiazol-2-yl]-1-methyl-1H-pyridin-2-one

MS APCI (+) m/z 442, 444 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 8.06 (s, 1H), 7.35 (dd, 1H), 7.29 (d, 1H), 7.08 (td, 1H), 3.75(t, 2H), 3.65 (s, 3H), 3.47 (t, 2H).

Example 141

5-[5-(2-Amino-ethylamino)-[1,3,4]oxadiazol-2-yl]-4-(4-bromo-2-fluorophenylamino)-3-fluoro-1-methyl-1H-pyridin-2-onehydrogen Chloride

MS APCI (+) m/z 441, 443 (M+, Br pattern) detected; ¹H NMR (400 mHz,DMSO) δ 8.94 (s, 1H), 8.17 (s, 1H), 8.06 (t, 1H), 7.95 (bs, 3H), 7.59(dd, 1H), 7.36 (d, 1H), 7.12 (td, 1H), 3.57 (s, 3H), 3.51 (q, 2H), 3.05(q, 2H).

Example 142

4-(4-Bromo-2-fluorophenylamino)-1,3-dimethyl-5-(1H-tetrazol-5-yl)-1H-pyridin-2-one

Step A: Preparation of3-{5-[4-(4-bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydro-pyridin-3-yl]-tetrazol-1-yl}-propionitrile:PPh₃ (83 mg, 0.32 mmol) was added to a stirred suspension of4-(4-bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-cyano-ethyl)-amide (51 mg, 0.12 mmol) in MeCN (1.5 mL). DIAD(0.065 mL, 0.31 mmol) and TMSN₃ (0.045 mL, 0.32) were added dropwise.After 22 hours, the reaction mixture was diluted with ethyl acetate andwashed with water. The aqueous layer was extracted with ethyl acetate.The combined organic extracts were dried (MgSO₄) and concentrated underreduced pressure. Purification by flash column chromatography gave cleandesired product (33 mg, 61%).

Step B: Preparation of4-(4-bromo-2-fluorophenylamino)-1,3-dimethyl-5-(1H-tetrazol-5-yl)-1H-pyridin-2-one:DBU (0.030 mL, 0.21 mmol) was added to a solution of3-{5-[4-(4-bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydro-pyridin-3-yl]-tetrazol-1-yl}-propionitrile(30 mg, 0.069 mmol) in methylene chloride (1.5 mL). After 2 hours, thereaction mixture was diluted with ethyl acetate and washed with 1 N HCl.The aqueous layer was extracted with ethyl acetate. The combined organicextracts were washed with brine, dried (MgSO₄) and concentrated underreduced pressure. Trituration with diethyl ether gave clean desiredproduct (20 mg, 77%); MS APCI (−) m/z 377, 379 (M−, Br pattern)detected; ¹H NMR (400 MHz, CD₃OD) δ 8.20 (s, 1H), 7.29 (dd, 1H), 7.13(dd, 1H), 6.63 (t, 1H), 3.65 (s, 3H), 1.91 (s, 3H).

Example 143

4-(4-Bromo-2-fluorophenylamino)-3-fluoro-1-methyl-5-(5-methyl-4H-[1,2,4]triazol-3-yl)-1H-pyridin-2-one

Step A: Preparation of4-(4-bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid N′-(1-imino-ethyl)-hydrazide: Ethyl acetimidate HCl salt (40 mg,0.32 mmol) and Et₃N (0.049 mL, 0.35 mmol) were added to a stirredsuspension of4-(4-bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid hydrazide (0.10 g, 0.27 mmol) in 2:1 THF:DMF (3 mL) at 0° C. After1.5 hours at 0° C. and 17 hours at room temperature, the reactionmixture was poured onto water, neutralized with dilute aqueous HCl andextracted with ethyl acetate. The combined organic extracts were dried(MgSO₄) and concentrated under reduced pressure. Trituration withmethylene chloride gave the desired product.

Step B: Preparation of4-(4-bromo-2-fluorophenylamino)-3-fluoro-1-methyl-5-(5-methyl-4H-[1,2,4]triazol-3-yl)-1H-pyridin-2-one:PPh₃ (0.12 g, 0.45 mmol), Et₃N (0.17 mL, 1.21 mmol), and CCl₄ (0.044 mL,0.45 mmol) were added to a stirred suspension of4-(4-bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid N′-(1-imino-ethyl)-hydrazide (0.073 g, 0.18 mmol) in methylenechloride (2 mL). The reaction mixture was stirred at 50° C. for 2 hours.After cooling to room temperature, the reaction mixture was diluted withethyl acetate, washed with water, dried (MgSO₄) and concentrated.Purification by flash column chromatography (4% MeOH in methylenechloride) gave clean desired product (30 mg, 50%); MS APCI (−) m/z 394,396 (M−, Br pattern) detected; ¹H NMR (400 mHz, CD₃OD) δ 8.16 (s, 1H),7.31 (dd, 1H), 7.25 (d, 1H), 7.01 (td, 1H), 3.67 (s, 3H), 2.51 (s, 3H).

Example 144

5-(5-Amino-[1,3,4]thiadiazol-2-yl)-4-(4-bromo-2-fluorophenylamino)-3-fluoro-1-methyl-1H-pyridin-2-one

A mixture of4-(4-bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (200 mg, 0.557 mmol), EDCI (214 mg, 1.11 mmol) and HOBt (151 mg,1.11 mol) were stirred in DMF (10 mL) for 30 minutes. Thiosemicarbazide(51 mg, 0.562 mmol) and Et₃N (0.116 mL, 1.5 mmol) were added. After 1hour, the reaction mixture was diluted with saturated aqueous NH₄Cl, andextracted with ethyl acetate. The combined organic extracts were dried(MgSO₄) and concentrated under reduced pressure. Purification by flashcolumn chromatography (5% to 10% MeOH in methylene chloride) gave 70 mgpartially pure intermediate adduct. PPh₃ (78 mg, 0.30 mmol), Et₃N (0.10mL, 0.74 mmol), and CCl₄ (0.029 mL, 0.30 mmol) were added to a stirredsuspension of intermediate adduct (40 mg, 0.093 mmol) in 1:1 methylenechloride:MeCN (4 mL). The reaction mixture was heated to 50° C. for 5hours. After cooling to room temperature, the reaction mixture wasdiluted with ethyl acetate, washed with water, dried (MgSO₄) andconcentrated under reduced pressure. Purification by flash columnchromatography (twice) (4% MeOH in methylene chloride) gave cleandesired product (10 mg, 33%); MS APCI (+) m/z 414, 416 (M+, Br pattern)detected; ¹H NMR (400 mHz, CD₃OD) δ 7.80 (s, 1H), 7.31 (dd, 1H), 7.25(d, 1H), 7.02 (td, 1H), 3.64 (s, 3H).

Example 145

5-(5-Amino-4H-[1,2,4]triazol-3-yl)-4-(4-bromo-2-fluorophenylamino)-3-fluoro-1-methyl-1H-pyridin-2-one

A mixture of4-(4-bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid hydrazide (100 mg, 0.268 mmol), 10% aqueous HCl (0.19 mL) andcyanamide (0.04 mL, 0.515 mmol) was heated to reflux for 3 days. Thereaction mixture was concentrated under reduced pressure, diluted withwater and washed with water. DMF (10 mL) was added to the aqueous layerand it was extracted with methylene chloride. The combined organicextracts were dried (MgSO₄) and concentrated under reduced pressure togive the desired intermediate adduct (35 mg). PPh₃ (76 mg, 0.29 mmol),Et₃N (0.10 mL, 0.74 mmol), and CCl₄ (0.028 mL, 0.29 mmol) were added toa stirred suspension of intermediate adduct (30 mg, 0.072 mmol) inmethylene chloride (2 mL). The reaction mixture was heated to 50° C. for5 hours. After cooling to room temperature, the reaction mixture wasdiluted with ethyl acetate, washed with water, dried (MgSO₄) andconcentrated under reduced pressure. Purification by flash columnchromatography (4% MeOH in methylene chloride) followed by methylenechloride trituration gave clean desired product (1 mg, 4%); MS APCI (+)m/z 397, 399 (M+, Br pattern) detected.

Example 146

N-[4-(4-Bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carbonyl]-C-phenyl-methanesulfonamide

N-[4-(4-Bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carbonyl]-C-phenyl-methanesulfonamidewas prepared from4-(4-bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid as follows. To a solution of4-(4-bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (0.040 mg, 0.113 mmol) in DMF (1.5 mL) was added1,1′-carbonyldiimidazole (0.074 mg, 0.456 mmol). After stirring for twohours, α-toluenesulfonamide (0.079 mg, 0.461 mmol) was added, followedby DBU (0.070 mL, 0.459 mmol). After stirring for 16 hours at roomtemperature, the reaction mixture was diluted with EtOAc and 1N HClsolution. The organic layer was separated and washed with brine. Theaqueous layer was extracted with EtOAc (2×) and washed with brine. Thecombined organic extracts were dried (MgSO₄) and concentrated underreduced pressure. Purification by flash column chromatography (2% MeOHin methylene chloride) gave 0.039 g (68%) clean desired product; MS APCI(−) m/z 506, 508 (M−, Br pattern) detected; ¹H NMR (400 MHz, CD₃OD) δ8.29 (s, 1H), 7.27 (m, 3H), 7.18 (d, 1H), 7.11 (m, 3H), 6.56 (t, 1H),4.44 (s, 2H), 3.54 (s, 3H), 1.62 (s, 3H).

Example 147

N-[4-(4-Bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carbonyl]-methanesulfonamide

N-[4-(4-Bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carbonyl]-methanesulfonamidewas prepared from4-(4-bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid as follows. To a solution of4-(4-bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (0.041 mg, 0.115 mmol) in DMF (1 mL) was added1,1′-carbonyldiimidazole (0.039 mg, 0.241 mmol). After stirring for twohours, methanetoluenesulfonamide (0.023 mg, 0.242 mmol) was added,followed by DBU (0.035 mL, 0.230 mmol). After stirring 16 hours at roomtemperature, the reaction mixture was diluted with EtOAc and 1N HClsolution. The organic layer was separated and washed with brine. Theaqueous layer was extracted with EtOAc (2×) and washed with brine. Thecombined organic extracts were dried (MgSO₄) and concentrated underreduced pressure. Purification by flash column chromatography (15% MeOHin methylene chloride) gave 0.028 g (57%) clean desired product; MS APCI(−) m/z 430, 432 (M−, Br pattern) detected; ¹H NMR (400 MHz, DMSO-d₆) δ11.13 (s, 1H), 8.25 (s, 1H), 7.49 (dd, 1H), 7.23 (d, 1H), 6.55 (t, 1H),3.46 (s, 3H), 2.83 (s, 3H), 1.56 (s, 3H).

Example 148

4-(2-Fluoro-4-methylphenylamino)-1,2,5-trimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Cyclopropylmethoxy-amide

Step A: Preparation of4-hydroxy-1,2,5-trimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acidethyl ester: A mixture of 2-methyl-3-oxo-pentanedioic acid diethyl ester(10.0 g, 46.3 mmol), 1,1-diethoxy-ethene (12.8 mL, 92.5 mmol) and sodiummethoxide (0.026 mg, 0.481 mmol) was heated to 85° C. for nine hours.The reaction mixture was cooled to room temperature and concentrated. Tothe resulting residue was added methylamine (1.91 mL, 55.5 mmol, 40%H₂O). After stirring at room temperature for 16 hours, the reactionmixture was diluted with diethyl ether and washed with water. Theaqueous phase was acidified to pH 1 with 10% HCl solution and extractedwith EtOAc. The organic layer was dried (MgSO₄) and concentrated.Trituration of the resulting residue with diethyl ether and flash columnchromatography (3% MeOH in methylene chloride) gave 3.55 g (34%) desiredproduct.

Step B: Preparation of4-Chloro-1,2,5-trimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acidethyl ester: Phosphorous oxychloride (20.0 mL, 216 mmol) was added to4-hydroxy-1,2,5-trimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acidethyl ester and heated to 80° C. After two hours, the reaction mixturewas concentrated under reduced pressure. The resulting residue waspoured onto ice and, carefully neutralized with saturated NaHCO₃, anddiluted with EtOAc. After stirring for 16 hours, the organic layer wasseparated and the aqueous layer was reextracted with EtOAc repeatedly.The pH of the aqueous layer was adjusted to pH 11 with saturated K₂CO₃and extracted with EtOAc (2×). The combined organic extracts were dried(MgSO₄) and concentrated under reduced pressure to give 3.42 g (89%)clean desired product.

Step C: Preparation of4-(2-fluoro-4-methylphenylamino)-1,2,5-trimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid ethyl ester: 2-Fluoro-4-methylphenylamine (0.259 g, 2.07 mmol),palladium (II) acetate (0.046 g, 0.205 mmol),rac-2,2-bis(diphenylphosphino)-1,1′-binaphthyl (0.192 g, 0.308 mmol),and cesium carbonate (1.00 g, 3.08 mmol) were added to a solution of4-chloro-1,2,5-trimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acidethyl ester (0.50 g, 2.05 mmol) in toluene (7 mL) in a sealed vial.After stirring 10 minutes, the mixture was heated to 80° C. After 24hours, the reaction mixture was cooled to room temperature and dilutedwith EtOAc. The resulting precipitate was filtered and washed withEtOAc. The filtrate was diluted with EtOAc and washed with water. Theaqueous layer was reextracted with EtOAc. The combined organic layerswere washed with brine, dried (Na₂SO₄) and concentrated. Purification byflash column chromatography (20:1 methylene chloride/MeOH) gave 0.048 g(71%) desired product.

Step D: Preparation of4-(2-fluoro-4-methylphenylamino)-1,2,5-trimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid cyclopropylmethoxy-amide: O-cyclopropylmethyl-hydroxylamine (0.046g, 0.527 mmol) was added to a solution of4-(2-fluoro-4-methylphenylamino)-1,2,5-trimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid ethyl ester (0.070 g, 0.211 mmol) in THF (2 mL). The solution wascooled to 0° C. and lithium bis(trimethylsilyl)amide (1.05 mL, 1 Msolution in hexanes) was added dropwise. The reaction mixture was warmedto room temperature. After stirring for 1 hour, the reaction wasquenched by addition of a saturated aqueous solution of NaHCO₃ andpartitioned between EtOAc and brine. The aqueous layer was reextractedwith EtOAc. The combined organic extracts were dried (Na₂SO₄) andconcentrated. Purification by flash column (30:1 methylenechloride/MeOH) gave 0.032 g (40%) desired product as a yellow solid; MSESI (+) m/z 374 (M+1) detected; ¹H NMR (400 MHz, CD₃OD) δ 6.91 (d, 1H),6.83 (d, 1H), 6.63 (t, 1H), 3.59 (s, 3H), 3.47 (d, 2H), 2.41 (s, 3H),2.27 (s, 3H), 1.86 (s, 3H) 0.99 (m, 1H) 0.48 (m, 2H) 0.18 (m, 2H). ¹⁹F(376 MHz, CD₃OD)-132.1 (s, 1F).

Example 149

4-(2-Fluoro-4-methylphenylamino)-1,2,5-trimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid (2-hydroxyethoxy)-amide

4-(2-Fluoro-4-methylphenylamino)-1,2,5-trimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-hydroxyethoxy)-amide was prepared as described in Example 148using the appropriate hydroxylamine, followed by deprotection usingstandard literature methods. MS ESI (+) m/z 364 (M+1) detected; ¹H NMR(400 MHz, CD₃OD) δ 6.91 (d, 1H), 6.83 (d, 1H), 6.63 (t, 1H), 3.80 (m,2H), 3.63 (m, 2H), 3.60 (s, 3H), 2.42 (s, 3H), 2.27 (s, 3H) 1.85 (s,3H). ¹⁹F (376 MHz, CD₃OD)-127.8 (s, 1F).

Example 150

4-(2-Fluoro-4-methylphenylamino)-1,3-dimethyl-6,7-dihydro-1H-pyrrolo[3,4-b]pyridine-2,5-dione

Step A: Preparation of2-bromomethyl-4-(2-fluoro-4-methylphenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid ethyl ester: To a solution of4-(2-fluoro-4-methylphenylamino)-1,2,5-trimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid ethyl ester (0.150 g, 0.451 mmol) in DMF (5 mL) was addedN-bromosuccinimide (0.084 g, 0.474 mmol). After stirring for 30 minutes,the reaction mixture was diluted with EtOAc, washed with water andbrine, dried (Na₂SO₄) and concentrated under reduced pressure to yield ayellow residue. Purification by flash column chromatography (methylenechloride) gave 0.122 g (66%) of a yellow residue.

Step B: Preparation of4-(2-fluoro-4-methylphenylamino)-1,3-dimethyl-6,7-dihydro-1H-pyrrolo[3,4-b]pyridine-2,5-dione:To a solution of2-bromomethyl-4-(2-fluoro-4-methylphenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid ethyl ester (0.016 g, 0.040 mmol) in MeOH (0.50 mL) was addedammonia (0.006 mL, 0.040 mmol, 7 M solution in MeOH). After stirring for2 hours at room temperature, the reaction mixture was heated to 40° C.for 8 hours. The resulting white precipitate was filtered to yield cleandesired product (0.005 g, 46%). MS ESI (+) m/z 303 (M+1) detected; ¹HNMR (400 MHz, DMSO) δ 8.16 (br s, 1H), 8.04 (br s, 1H), 6.81-6.94 (m,3H), 4.33 (s, 2H), 3.45 (s, 3H), 2.33 (s, 3H), 1.63 (s, 3H). ¹⁹F (376MHz, DMSO)-127.1 (s, 1F).

Example 151

4-(4-Bromo-2-fluorophenylamino)-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxylicAcid Cyclopropylmethoxy-amide

Step A: Preparation of 3-oxo-2-(phenyl-hydrazono)-pentanedioic aciddimethyl ester: 3-oxo-2-(phenyl-hydrazono)-pentanedioic acid dimethylester was prepared from 3-oxo-pentanedioic acid dimethyl ester (7.02 mL,45.9 mmol) according to the procedure of Schober et al. (J. HeterocylicChem. 1989, 26, 169) to give 8.81 g (72%) of the desired product.

Step B: Preparation of4-hydroxy-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxylic acid methylester: A mixture of 3-oxo-2-(phenyl-hydrazono)-pentanedioic aciddimethyl ester (4.38 g, 15.7 mmol) in 1,2-dichlorobenzene (15 mL) wasrefluxed. After 20 hours, the reaction mixture was concentrated underreduced pressure to give 3.83 g (99%) of the desired product.

Step C: Preparation of4-chloro-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxylic acid methylester: A mixture of4-hydroxy-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxylic acid methylester (3.83 g, 15.6 mmol) and phosphorous oxychloride (50 mL) was heatedto 85° C. After 20 hours, the reaction mixture was concentrated underreduced pressure. The resulting residue was quenched with water. Theprecipitate was filtered and dissolved in EtOAc, dried (MgSO₄) andconcentrated under reduced pressure to yield 3.44 g (84%) of desiredproduct.

Step D: Preparation of4-(4-bromo-2-fluorophenylamino)-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxylicacid: To a mixture of4-chloro-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxylic acid methylester (0.250 g, 0.944 mmol) in 1,2-dichlorobenzene (3.8 mL) was added4-bromo-2-fluoro aniline (0.561 g, 3.78 mmol), and cesium carbonate(0.615 mg, 1.89 mmol). The reaction mixture was heated to reflux. After1 hour, the reaction mixture was cooled to room temperature. Water wasadded and the mixture was diluted with EtOAc. The aqueous layer wasseparated, acidified with 10% HCl solution, and extracted with EtOAc.The combined organic layers were dried (MgSO4), concentrated underreduced pressure, and triturated to give 0.153 g (43%) of the desiredproduct.

Step E. Preparation of4-(4-Bromo-2-fluorophenylamino)-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxylicacid cyclopropylmethoxy-amide.4-(4-Bromo-2-fluorophenylamino)-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxylicacid cyclopropylmethoxy-amide was prepared from4-(4-bromo-2-fluorophenylamino)-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxylicacid as described in Example 2. MS APCI (−) m/z 471, 473 (M−, Brpattern) detected; ¹H NMR (400 MHz, CD₃OD-CDCl₃) δ 7.50 (m, 8H), 6.12(s, 1H), 3.78 (d, 2H), 1.18 (m, 1H), 0.59 (q, 2H), 0.32 (q, 2H).

Example 152

4-(4-Bromo-2-fluorophenylamino)-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxylicAcid (2-hydroxyethoxy)-amide

Prepared from4-(4-bromo-2-fluorophenylamino)-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxylicacid as described in Example 3. MS APCI (−) m/z 461, 463 (M−, Brpattern) detected; ¹H NMR (400 MHz, CD₃OD) δ 7.51 (m, 8H), 6.09 (s, 1H),4.04 (t, 2H), 3.77 (t, 2H).

Example 153

2-(4-Bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid

Step A. Preparation of 2-chloro-6-oxo-1,6-dihydropyridine-3-carboxylicacid: 2-Chloro-6-oxo-1,6-dihydropyridine-3-carboxylic acid was preparedfrom dichloronicotinic acid (3.00 g, 15.6 mmol, Aldrich) according tothe procedure described in U.S. Pat. No. 3,682,932 (1972) to yield 1.31g (48%) of the desired product.

Step B. Preparation of2-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methylester: To a solution of 2-chloro-6-oxo-1,6-dihydropyridine-3-carboxylicacid (0.644 g, 3.71 mmol) in DMF (20 mL) was added lithium hydride (95%,0.078 g, 9.28 mmol) and the reaction mixture was stirred for 40 minutesunder N₂. Methyl iodide (0.508 mL, 1.16 g, 8.16 mmol) was then added andthe reaction mixture was stirred for an additional 45 minutes. Thereaction mixture was quenched with 2 M HCl until the pH was 6-7. Thereaction mixture was diluted with EtOAc and saturated NaCl and thelayers separated. The aqueous layer was back extracted with EtOAc (1×).The combined organic layers were dried (Na₂SO₄) and concentrated underreduced pressure to yield a crude yellow solid. HPLC analysis showed twoproducts in a 4:1 ratio that were separated by flash columnchromatography (methylene chloride/EtOAc, 15:1 to 10:1) to give 0.466 g(62%) pure desired product as a white crystalline solid. The minorproduct was also isolated as a pale yellow crystalline solid andidentified as the regioisomer 2-chloro-6-methoxy-nicotinic acid methylester.

Step C. Preparation of2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid methyl ester: To a solution of 4-bromo-2-fluorophenylamine (0.192g, 1.01 mmol) in THF (5 mL) at −78° C. under N₂ was added lithiumbis(trimethylsilyl)amide (1.50 mL, 1.50 mmol, 1 M solution in hexanes)dropwise. The reaction mixture was stirred for one hour at −78° C.2-Chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methylester (0.202 g, 1.00 mmol) was then added dropwise as a solution in THF(5 mL) and the reaction mixture was stirred for one hour at −78° C. Thereaction mixture was quenched by the addition of H₂O and the pH wasadjusted to pH 7 with saturated NH₄Cl and then diluted with EtOAc. Theorganic layer was separated and washed with saturated NaCl, dried(Na₂SO₄), and concentrated under reduced pressure. Purification by flashcolumn chromatography (methylene chloride/EtOAc, 15:1) gave 0.232 g(65%) pure desired product as a white crystalline solid.

Step D. Preparation of2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid: To a solution of2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid methyl ester in MeOH (1.5 mL) was added 1 M NaOH (800 uL, 0.902mmol). The reaction mixture was stirred at 60° C. for 4 hours and thenat room temperature for 16 hours. The reaction mixture was diluted withH₂O, acidified with 2 M HCl until the pH was 1-2, and then diluted withEtOAc. The organic layer was separated and washed with saturated NaCl,dried (Na₂SO₄), and concentrated under reduced pressure to yield 0.053 g(97%) desired product as a pale orange solid. MS ESI (+) m/z 341, 343(M+, Br pattern) detected; ¹H NMR (400 MHz, DMSO-d₆) δ 13.08 (s, 1H),10.0 (s, 1H), 7.87 (d, 1H), 7.65 (d, 1H), 7.35 (d, 1H), 6.95 (t, 1H),6.16 (d, 1H), 3.19 (s, 3H).

In the foregoing examples, a variety of anilines can be used in place of4-bromo-2-fluorophenylamine in Step C of Example 153.

Example 154

2-(4-Bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Cyclopropylmethoxy-amide

A mixture of2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (0.022 g, 0.064 mmol), EDCI (0.019 g, 0.097 mmol), and HOBt (0.019g, 0.097 mmol) in DMA (1 mL) was stirred for 30 minutes at roomtemperature under N₂. O-Cyclopropylmethyl-hydroxylamine (0.017 g, 0.19mmol) was added followed by Et₃N (0.022 mL, 0.016 g, 0.16 mmol). Afterthe reaction mixture was stirred for 16 hours at room temperature, itwas diluted with EtOAc and washed with saturated NH₄Cl solution,saturated NaHCO₃ solution and saturated NaCl. The organic layer wasdried (Na₂SO₄) and concentrated under reduced pressure. Purification byflash column chromatography (methylene chloride/methanol, 20:1) gave0.015 g (57%) pure desired product as a yellow solid. MS APCI (−) m/z410, 411 (M−, Br pattern) detected; ¹H NMR (400 MHz, DMSO-d₆) δ 11.4 (s,1H), 9.81 (s, 1H), 7.58 (m, 2H), 7.28 (d, 1H), 6.82 (t, 1H), 6.17 (d,1H), 3.46 (d, 2H), 3.22 (s, 3H), 0.99 (m, 1H), 0.48 (m, 2H), 0.18 (m,2H).

Example 155

2-(2-Fluoro-4-methylphenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid (2-hydroxyethoxy)-amide

Step A. Preparation of2-(2-fluoro-4-methylphenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-vinyloxyethoxy)-amide: To a solution of2-(2-fluoro-4-methylphenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid methyl ester (0.050 g, 0.17 mmol) in THF (1.5 mL) under N₂ wasadded O-(2-vinyloxy-ethyl)-hydroxylamine (0.044 g, 0.43 mmol). Thesolution was cooled to 0° C. and lithium bis(trimethylsilyl)amide (0.86mL, 0.86 mmol, 1 M solution in hexanes) was added dropwise. The reactionmixture was warmed to room temperature. After stirring for 40 minutes,the reaction mixture was quenched by the addition of NaHCO₃ andpartitioned between EtOAc and saturated NaCl. The layers were separatedand the aqueous layer was reextracted with EtOAc. The combined organicextracts were dried (Na₂SO₄) and concentrated under reduced pressure.Purification by flash column chromatography (methylenechloride/methanol, 20:1) gave 0.048 g (77%) pure desired product as anoff-white foamy solid.

Step B. Preparation of2-(2-fluoro-4-methylphenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-hydroxyethoxy)-amide: To a solution of2-(2-fluoro-4-methylphenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-vinyloxyethoxy)-amide (0.048 g, 0.13 mmol) in ethanol (5 mL) wasadded aqueous 2 M HCl (0.332 mL, 0.664 mmol). The reaction mixture wasstirred for 16 hours at room temperature. The pH of the reaction mixturewas adjusted with 1 M NaOH until 7. The reaction mixture was dilutedwith EtOAc and H₂O. The organic layer was separated and washed withsaturated NaCl, dried (Na₂SO₄), and concentrated under reduced pressureto yield 0.044 g (100%) pure desired product as a pale yellow foamysolid. MS ESI (+) m/z 336 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 10.3(s, 1H), 8.46 (s, 1H), 7.38 (d, 1H), 6.96-6.87 (m, 2H), 6.76 (t, 1H),6.18 (d, 1H), 4.04 (m, 2H), 3.93 (br s, 1H), 3.75 (br s, 2H), 3.20 (s,3H), 2.33 (s, 3H).

Any of the hydroxylamines used in the foregoing examples can be coupledas described in Example 154 or Example 155. In some instances, a finaldeprotection step may be required. These deprotections can beaccomplished by standard literature methods. Example 155 is one suchexample in which a final deprotection step is required.

Example 156

2-(4-Bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid (2-hydroxyethoxy)-amide

Step A. Preparation of2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-vinyloxyethoxy)-amide:2-(4-Bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (0.020 g, 0.059 mmol) was coupled as described previously inExample 154 using O-(2-vinyloxy-ethyl)-hydroxylamine to yield 0.015 g(60%) pure desired product as a yellow solid.

Step B. Preparation of2-(4-Bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-hydroxyethoxy)-amide:2-(4-Bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-vinyloxyethoxy)-amide (0.015 g, 0.035 mmol) was deprotected asdescribed previously in Step B of Example 155 to yield 0.010 g (70%)pure desired product as a dark yellow solid.

MS ESI (+) m/z 400, 402 (M+, Br pattern) detected; ¹H NMR (400 MHz,CDCl₃) δ 10.3 (s, 1H), 9.11 (s, 1H), 7.47 (d, 1H), 7.32 (d, 1H), 7.23(d, 1H), 6.70 (t, 1H), 6.22 (d, 1H), 4.04 (br s, 2H), 3.75 (br s, 2H)3.24 (s, 3H).

Example 157

2-(2-Fluoro-4-iodophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Methoxy-amide

2-(2-Fluoro-4-iodophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid methyl ester was coupled as described previously in Example 155using O-methyl-hydroxylamine. MS ESI (+) m/z 418 (M+1) detected.

Example 158

2-(4-Bromo-2-fluorophenylamino)-1-ethyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid (2-hydroxyethoxy)-amide

2-Chloro-6-oxo-1,6-dihydropyridine-3-carboxylic acid was converted to2-(4-bromo-2-fluorophenylamino)-1-ethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid methyl ester following the procedures described in Steps B-C ofExample 153 using ethyl iodide in Step B of Example 153.2-(4-Bromo-2-fluorophenylamino)-1-ethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid methyl ester was then coupled as described in Example 155 to yieldthe desired product as a tan solid. MS APCI (+) m/z 414, 416 (M+, Brpattern) detected; ¹H NMR (400 MHz, CD₃OD) δ 7.59 (d, 1H), 7.38 (d, 1H),7.24 (d, 1H), 6.77 (t, 1H), 6.33 (d, 1H), 4.16 (q, 2H), 3.73 (m, 2H),3.59 (m, 2H), 1.21 (t, 3H).

Example 159

2-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid (2-hydroxyethoxy)-amide

2,6-Dichloro-5-fluoro-nicotinic acid (Lancaster Synthesis) was convertedto2-(4-bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid methyl ester following the procedures described in Steps A-C ofExample 153.2-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid methyl ester was then coupled as described in Example 155 to yieldthe desired product as a yellow solid. MS ESI (+) m/z 418, 420 (M+, Brpattern) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.32 (dd, 1H), 7.29-7.19(m, 2H), 6.61 (t, 1H), 4.06 (m, 2H), 3.76 (m, 2H), 3.33 (s, 3H), 3.32(s, 3H).

Example 160

5-Bromo-2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid

Step A. Preparation of5-bromo-2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid methyl ester: To a solution of2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid methyl ester (0.390 g, 1.34 mmol) in DMF (10 mL) was addedN-bromosuccinimide (0.263, 1.48 mmol). The reaction mixture was stirredat room temperature for 25 minutes and then quenched with saturatedsodium bisulfite. The reaction mixture was diluted with H₂O andpartitioned between EtOAc/diethyl ether and saturated NaCl. The layerswere separated and the aqueous layer was reextracted with EtOAc (1×).The combined organic layers were dried (Na₂SO₄) and concentrated underreduced pressure. Purification by flash column chromatography (methylenechloride/EtOAc, 15:1) gave 0.424 g (85%) pure desired product as alavender foamy solid.

Step B. Preparation of5-bromo-2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid: To a suspension of5-bromo-2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid methyl ester (0.030 g, 0.069 mmol) in methanol (1 mL) was added 1 MNaOH (0.346 mL, 0.346 mmol). The reaction mixture was heated to 60° C.for 12 hours. The reaction mixture was diluted with H₂O and the pH wasadjusted with 1 M HCl until 1-2. Solids precipitated out of solution,which were collected, washed with H₂O and dried under vacuum to yield0.021 g (72%) pure desired product as a pale yellow solid. MS ESI (+)m/z 421, 423 (M+, Br pattern) detected; ¹H NMR (400 MHz, DMSO-d₆) δ 13.3(br s, 1H), 9.93 (s, 1H), 8.21 (s, 1H), 7.66 (d, 1H), 7.34 (d, 1H), 7.05(t, 1H), 3.18 (s, 3H).

Example 161

5-Bromo-2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicAcid (2-hydroxyethoxy)-amide

5-Bromo-2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (0.018 g, 0.043 mmol) was converted to the desired productfollowing the procedures described in Example 156 to yield 0.009 g (45%)pure desired product as a dark yellow solid. MS ESI (+) m/z 480, 482(M+, Br pattern) detected;

¹H NMR (400 MHz, CDCl₃) δ 8.00 (s, 1H), 7.32 (m, 1H), 7.24 (d, 1H), 6.69(t, 1H), 3.99 (m, 2H), 3.73 (m, 2H), 3.32 (s, 3H).

Example 162

2-(4-Bromo-2-fluorophenylamino)-6-oxo-1,6-dihydropyridine-3-carboxylicAcid

Step A. Preparation of2-(4-bromo-2-fluorophenylamino)-6-chloro-nicotinic acid: To a solutionof 4-bromo-2-fluorophenylamine (10.4 g, 54.7 mmol) in THF (25 mL) at−78° C. under N₂ was added lithium bis(trimethylsilyl)amide (83.3 mL,83.3 mmol, 1 M solution in hexanes) dropwise over 15 minutes. Thereaction mixture was stirred for one hour at −78° C.2,6-Dichloro-nicotinic acid (5.00 g, 26.0 mmol) was then added dropwiseas a solution in THF (15 mL) and the reaction mixture was allowed towarm from −78° C. to room temperature and stir for 16 hours. Thereaction mixture was quenched by the addition of H₂O and the pH wasadjusted to 0-2 with 6 N HCl and then diluted with EtOAc. The organiclayer was separated and washed with H₂O, saturated NaCl, dried (Na₂SO₄),and concentrated under reduced pressure. The crude product wastriturated several times with ethyl acetate and the resulting solid wascollected, washed with dichloromethane and dried under vacuum to yield7.50 g (83%) pure desired product as a dark pink solid.

Step B. Preparation of2-(4-bromo-2-fluorophenylamino)-6-chloro-nicotinic acid methyl ester: Toa suspension of 2-(4-bromo-2-fluorophenylamino)-6-chloro-nicotinic acid(5.00 g, 14.5 mmol) in methanol/benzene (1:1, 100 mL) under N₂ was added(trimethylsilyl)diazomethane (2.0 M solution in hexanes) dropwise untilthe bubbling caused by gas evolution ceased. Solids precipitated out ofsolution. The reaction was allowed to stir for 1 hour. Excess(trimethylsilyl)diazomethane was quenched by the dropwise addition ofglacial acetic acid. The precipitated solids were filtered and washedwith methanol. The filtrate was concentrated to a smaller volume andadditional solids precipitated out of solution that were filtered andwashed with methanol. The solids were combined and dried under vacuum toyield 4.82 g (93%) of pure desired product as a dark pink solid.

Step C. Preparation of2-(4-bromo-2-fluorophenylamino)-6-methoxy-nicotinic acid methyl ester:To a mixture of 2-(4-bromo-2-fluorophenylamino)-6-chloro-nicotinic acidmethyl ester (2.00 g, 5.56 mmol) and sodium methoxide (0.791 g, 13.9mmol) was added MeOH (50 mL) to give a slurry that was stirred at 60-65°C. for 16 hours under N₂. Additional sodium methoxide (0.791 g, 13.9mmol) was added and the reaction mixture was allowed to stir another 3days at 60-65° C. The reaction mixture was cooled to room temperatureand glacial acetic acid was added dropwise until the pH was 7. Theresulting suspension was filtered and washed with H₂O to yield a pinksolid that was collected and dried under vacuum to yield 1.74 g (88%)pure desired product.

Step D. Preparation of2-(4-bromo-2-fluorophenylamino)-6-oxo-1,6-dihydropyridine-3-carboxylicacid methyl ester: To2-(4-bromo-2-fluorophenylamino)-6-methoxy-nicotinic acid methyl ester(1.00 g, 2.82 mmol) in a sealed flask was added glacial acetic acid (10mL) and HBr (10 mL, 48 wt % in H₂O). The reaction mixture was stirred at90-95° C. for 2 hours and then cooled to room temperature. The reactionmixture was diluted with EtOAc and washed with H₂O, saturated NaHCO₃,saturated NaCl, dried (Na₂SO₄) and concentrated under reduced pressure.The crude product was triturated twice with dichloromethane/methanol andthe resulting solid was collected and dried under vacuum to yield 0.756g (79%) pure desired product as a white solid.

Step E. Preparation of2-(4-bromo-2-fluorophenylamino)-6-oxo-1,6-dihydropyridine-3-carboxylicacid: To a suspension of2-(4-bromo-2-fluorophenylamino)-6-oxo-1,6-dihydropyridine-3-carboxylicacid methyl ester (0.050 g, 0.147 mmol) in methanol (1.5 mL) was added 1M NaOH (1.47 mL, 1.47 mmol). The reaction mixture was stirred at 75-80°C. for 2 days. The reaction mixture was diluted with H₂O and the pH wasadjusted with 1 M HCl until 1-2. The reaction mixture was diluted withEtOAc and washed with saturated NaCl, dried (Na₂SO₄), and concentratedunder reduced pressure. The crude product was triturated with diethylether/dichloromethane and the resulting solid was collected and driedunder vacuum to yield 0.033 g (69%) pure desired product as a yellowsolid. MS ESI (+) m/z 327, 329 (M+, Br pattern) detected; ¹H NMR (400mHz, DMSO-d₆) δ 13.1 (br s, 1H), 11.5 (s, 1H), 10.9 (s, 1H), 8.77 (br s,1H), 8.10 (d, 1H), 7.59 (d, 1H), 7.35 (d, 1H) 6.16 (m, 1H).

Example 163

2-(4-Bromo-2-fluorophenylamino)-6-oxo-1,6-dihydropyridine-3-carboxylicAcid Cyclopropylmethoxy-amide

2-(4-Bromo-2-fluorophenylamino)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (0.025 g, 0.076 mmol) was converted to the desired productfollowing the procedure described in Example 154 to yield 0.023 g (76%)pure desired product as a pale yellow solid.

MS ESI (+) m/z 396, 398 (M+, Br pattern) detected; ¹H NMR (400 mHz,DMSO-d₆) δ 11.6 (s, 1H), 11.3 (s, 1H), 11.2 (s, 1H), 9.74 (br s, 1H),7.90 (d, 1H), 7.56 (d, 1H), 7.32 (d, 1H), 6.13 (d, 1H) 3.70 (d, 2H) 1.10(m, 1H), 0.54 (m, 2H), 0.27 (m, 2H).

Example 164

4-(2-Fluoro-4-methylphenylamino)-1,3-dimethyl-7,8-dihydro-1H,6H-pyrido[2,3-d]pyridazine-2,5-dione

To a solution of2-bromomethyl-4-(2-fluoro-4-methylphenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid ethyl ester (1 equivalent) in MeOH is added hydrazine (1.10equivalents). After stirring for 2 hours at room temperature, thereaction mixture is heated to 40° C. for 8 hours. The reaction mixtureis diluted with EtOAc and washed with water. The organic layer is driedover MgSO₄, filtered, and concentrated in vacuo to give the crudematerial that is purified by trituration or flash column chromatographyto afford the desired product as necessary.

Example 165

4-(2-Fluoro-4-methylphenylamino)-1,3,8-trimethyl-1H,6H-pyrido[2,3-d]pyridazine-2,5-dione

Step A: Preparation of2-bromo-4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid ethyl ester: To a solution of4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethylester (1.00 equivalent) in DMF is added NBS (1.20 equivalents) at roomtemperature. After stirring for 16 hours at room temperature, thereaction mixture is diluted with EtOAc and washed with water. Theorganic layer is dried over MgSO₄, filtered, and concentrated in vacuoto give the crude material that is purified by trituration or flashcolumn chromatography to afford the desired product as necessary.

Step B: Preparation of4-chloro-1,5-dimethyl-6-oxo-2-trimethylsilanylethynyl-1,6-dihydropyridine-3-carboxylicacid ethyl ester: To a mixture of2-bromo-4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid ethyl ester (1.00 equivalent), trimethylsilylacetylene (1.20equivalents) and iPr₂NH (2.00 equivalents) in THF is added CuI (0.10equivalents) followed by Pd(PPh₃)₂Cl₂ (0.10 equivalents). After stirringthe reaction mixture at reflux for 16 hours, it is cooled to roomtemperature and diluted with ethyl acetate. The organic layer is washedwith saturated NH₄Cl solution and brine, dried (MgSO₄) and concentratedunder reduced pressure. The desired product is obtained by flash columnchromatography as necessary.

Step C: Preparation of2-acetyl-4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid ethyl ester: A mixture of4-chloro-1,5-dimethyl-6-oxo-2-trimethylsilanylethynyl-1,6-dihydropyridine-3-carboxylicacid ethyl ester (1.00 equivalent), HgSO₄ (1.00 equivalent) and H₂SO₄(2.00 equivalents) in ˜6:1 acetone:water is refluxed for 3 hours. Thereaction mixture is cooled to room temperature and concentrated underreduced pressure. The residue is diluted with a mixture of THF and ethylacetate and washed with water and brine. The organic layer is dried(MgSO₄) and concentrated under reduced pressure. The desired product isobtained by flash column chromatography as necessary.

Step D: Preparation of2-acetyl-4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid: To a solution of2-acetyl-4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid ethyl ester (1.00 equivalent) in THF:water (4:1) is added 1 Maqueous LiOH solution (2.05 equivalents). After 30 minutes, the reactionmixture is acidified to pH 1 with 1 N HCl solution and extracted withethyl acetate. The combined organic extracts are dried (MgSO₄) andconcentrated under reduced pressure to give the desired product which isused directly without further purification.

Step E: Preparation of4-chloro-1,3,8-trimethyl-1H,6H-pyrido[2,3-d]pyridazine-2,5-dione: To asolution of2-acetyl-4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (1 equivalent) and hydrazine monohydrate (3.30 equivalents) in THFis added 1 N HCl (0.80 equivalents). After 16 hours, the reactionmixture is diluted with ethyl acetate, washed with water and brine,dried (MgSO₄) and concentrated under reduced pressure. The desiredproduct purified by trituration or flash column chromatography to affordthe desired product as necessary.

Step F: Preparation of4-(2-fluoro-4-methylphenylamino)-1,3,8-trimethyl-1H,6H-pyrido[2,3-d]pyridazine-2,5-dione:2-Fluoro-4-methylphenylamine (1.10 equivalents), palladium (II) acetate(0.10 equivalents), rac-2,2-bis(diphenylphosphino)-1,1′-binaphthyl (0.15equivalents), and cesium carbonate (1.50 equivalents) are added to asolution of4-chloro-1,3,8-trimethyl-1H,6H-pyrido[2,3-d]pyridazine-2,5-dione (1.00equivalent) in toluene in a sealed vial. After stirring 10 minutes, themixture is heated to 80° C. After 24 hours, the reaction mixture iscooled to room temperature and diluted with EtOAc. The resultingprecipitate is filtered and washed with EtOAc. The filtrate is dilutedwith EtOAc and washed with water. The aqueous layer is reextracted withEtOAc. The combined organic layers are washed with brine, dried (Na₂SO₄)and concentrated. Purification by flash column chromatography gives thedesired product.

The foregoing description is considered as illustrative only of theprinciples of the invention. Further, since numerous modifications andchanges will be readily apparent to those skilled in the art, it is notdesired to limit the invention to the exact construction and processshown as described above. Accordingly, all suitable modifications andequivalents may be resorted to falling within the scope of the inventionas defined by the claims that follow.

The words “comprise,” “comprising,” “include,” “including,” and“includes” when used in this specification and in the following claimsare intended to specify the presence of stated features, integers,components, or steps, but they do not preclude the presence or additionof one or more other features, integers, components, steps, or groupsthereof.

1. A compound including resolved enantiomers, diastereomers, solvatesand pharmaceutically acceptable salts thereof, said compound having theformula:

where R¹, R², R⁸ and each R⁹ are independently hydrogen, halogen, cyano,nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, azido, —SR¹¹, —OR³, —C(O)R³,—C(O)OR³, —NR⁴C(O)OR⁶, —OC(O)R³, —NR⁴SO₂R⁶, —SO₂NR³R⁴, —NR³R⁴C(O)R³,—C(O)NR³R⁴, —NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —NR³R⁴, C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl,—S(O)_(j)(C₁-C₆ alkyl), —S(O)_(j)(CR⁴R⁵)_(m)-aryl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl,—O(CR⁴R⁵)_(m)-aryl, —NR⁴(CR⁴R⁵)_(m)-aryl, —O(CR⁴R⁵)_(m)-heteroaryl,—NR⁴(CR⁴R⁵)_(m)-heteroaryl, —O(CR⁴R⁵)_(m)-heterocyclyl or—NR⁴(CR⁴R⁵)_(m)-heterocyclyl, wherein any of said alkyl, alkenyl,alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl portions are optionally substitutedwith one or more groups independently selected from oxo (with theproviso that it is not substituted on an aryl or heteroaryl), halogen,cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido—NR⁴SO₂R⁶, —SO₂NR³R⁴, —C(O)R³, —C(O)R³, —OC(O)R³, —NR⁴C(O)OR⁶,—NR⁴C(O)R³, —C(O)NR³R⁴, —NR³R⁴, —NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —OR³,aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl, and wherein said aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl or heterocyclylalkyl rings may be furthersubstituted with one or more groups selected from halogen, hydroxyl,cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl,C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, C₃-C₆heterocycloalkyl, NR³R⁴ and OR³; R⁷ is hydrogen, trifluoromethyl, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, or heterocyclylalkyl, wherein any of said alkyl, alkenyl,alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl portions are optionally substitutedwith one or more groups independently selected from oxo (with theproviso that it is not substituted on an aryl or heteroaryl), halogen,cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl,difluoromethoxy, trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴, —SO₂NR¹¹R¹²,—C(O)R¹¹, C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴, —NR¹¹C(O)R¹²,—C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴, —NR¹¹R¹², —NR¹¹C(O)NR¹²R¹³,—NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl,C₃-C₁₀ cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl, and wherein said aryl, heteroaryl,arylalkyl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl rings maybe further substituted with one or more groups selected from halogen,hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl,trifluoromethyl, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆cycloalkyl, C₃-C₆ heterocycloalkyl, NR³R⁴ and OR³; R³ is hydrogen,trifluoromethyl, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀cycloalkyl, C₃-C₁₀ cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, heterocyclylalkyl, phosphate or an aminoacid residue, wherein any of said alkyl, alkenyl, alkynyl, cycloalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl andheterocyclylalkyl portions are optionally substituted with one or moregroups independently selected from oxo (with the proviso that it is notsubstituted on an aryl or heteroaryl), halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR¹¹SO₂R₁₄,—SO₂NR¹¹R¹², —C(O)R¹¹, C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹², —NR¹¹C(O)R¹⁴,—C(O)NR¹¹R¹², —SR¹⁴, —S(O)R¹¹, —SO₂R¹⁴, —NR¹⁴R¹², —NR¹¹C(O)NR¹⁴R¹³,—NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl, or R³ and R⁴ together with the atomto which they are attached form a 4 to 10 membered carbocyclic,heteroaryl or heterocyclic ring, wherein any of said carbocyclic,heteroaryl or heterocyclic rings are optionally substituted with one ormore groups independently selected from halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴,—SO₂NR¹¹R¹², —C(O)R¹¹, C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴, —NR¹¹C(O)R¹²,—C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹², —SO₂R¹⁴, —NR¹⁴R¹¹, —NR¹¹C(O)NR¹²R¹³,—NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl; R⁴ and R⁵ independently arehydrogen or C₁-C₆ alkyl, or R⁴ and R⁵ together with the atom to whichthey are attached form a 4 to 10 membered carbocyclic, heteroaryl orheterocyclic ring, wherein said alkyl or any of said carbocyclic,heteroaryl and heterocyclic rings are optionally substituted with one ormore groups independently selected from halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴,—SO₂NR¹¹R¹², —C(O)R¹¹, C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴, —NR¹¹C(O)R¹²,—C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴, —NR¹¹R¹², —NR¹¹C(O)NR¹²R¹³,—NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl; R⁶ is trifluoromethyl, C₁-C₁₀alkyl, C₃-C₁₀ cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl or heterocyclylalkyl, wherein any of said alkyl,cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyland heterocyclylalkyl portions are optionally substituted with one ormore groups independently selected from oxo (with the proviso that it isnot substituted on an aryl or heteroaryl), halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴,—SO₂R¹¹R¹², —C(O)R¹¹, C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴, —NR¹¹C(O)R¹²,—C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, SO₂R¹⁴, —NR¹¹R¹², —NR¹¹C(O)NR¹¹R¹¹,—NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl; R¹¹, R¹² and R¹³ independently arehydrogen, lower alkyl, lower alkenyl, aryl and arylalkyl, and R¹⁴ islower alkyl, lower alkenyl, aryl and arylalkyl; or any two of R¹¹, R¹²,R¹³ or R¹⁴ together with the atom to which they are attached form a 4 to10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein any ofsaid alkyl, alkenyl, aryl, arylalkyl carbocyclic rings, heteroaryl ringsor heterocyclic rings are optionally substituted with one or more groupsindependently selected from halogen, cyano, nitro, trifluoromethyl,difluoromethoxy, trifluoromethoxy, azido, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; m is 0, 1, 2, 3, 4or 5; and j is 0, 1 or
 2. 2. A composition comprising a compound ofclaim 1 and a pharmaceutically acceptable carrier.
 3. A compoundincluding resolved enantiomers, diastereomers, solvates andpharmaceutically acceptable salts thereof, said compound having theformula:

where R¹, R², R⁸ and R⁹ are independently hydrogen, halogen, cyano,nitro, trifluoromethyl, difluoromethoxy, difluoromethyl, fluoromethyl,fluoromethoxy, trifluoromethoxy, azido, —SR¹¹, —OR³, —C(O)R³, —C(O)OR³,—NR⁴C(O)OR⁶, —OC(O)R³, —NR⁴SO₂R⁶, —SO₂NR³R⁴, —NR⁴C(O)R³, —C(O)NR³R⁴,—NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —NR³R⁴, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl,C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl,—S(O)_(j)(C₁-C₆ alkyl), —S(O)_(j)(CR⁴R⁵)_(m)-aryl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl,—O(CR⁴R⁵)_(m)-aryl, —NR⁴(CR⁴R⁵)_(m)-aryl, —O(CR⁴R⁵)_(m)-heteroaryl,—NR⁴(CR⁴R⁵)_(m)-heteroaryl, —O(CR⁴R⁵)_(m)-heterocyclyl or—NR⁴(CR⁴R⁵)_(m)-heterocyclyl, wherein any of said alkyl, alkenyl,alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl portions are optionally substitutedwith one or more groups independently selected from oxo (with theproviso that it is not substituted on an aryl or heteroaryl), halogen,cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,—NR⁴SO₂R⁶, —SO₂NR³R⁴, —C(O)R³, —C(O)OR³, —OC(O)R³, —NR⁴C(O)OR⁶,—NR⁴C(O)R³, —C(O)NR³R⁴, —NR³R⁴, —NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —OR³,aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl, and wherein said aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl or heterocyclylalkyl rings may be furthersubstituted with one or more groups selected from halogen, hydroxyl,cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl,C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, C₃-C₆heterocycloalkyl, NR³R⁴ and OR³; each R⁷ is hydrogen, trifluoromethyl,C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, or heterocyclylalkyl, wherein any of said alkyl, alkenyl,alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl portions are optionally substitutedwith one or more groups independently selected from oxo (with theproviso that it is not substituted on an aryl or heteroaryl), halogen,cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl,difluoromethoxy, trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴, —SO₂NR¹¹R¹²,—C(O)R¹¹, C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴, —NR¹¹C(O)R¹²,—C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴, —NR¹¹R¹², NR¹¹C(O)NR¹²R¹³,—NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl,C₃-C₁₀ cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl, and wherein said aryl, heteroaryl,arylalkyl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl rings maybe further substituted with one or more groups selected from halogen,hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl,trifluoromethyl, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆cycloalkyl, C₃-C₆ heterocycloalkyl, NR³R⁴ and OR³; each R¹⁰ isindependently hydrogen, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —C(O)R³, —C(O)OR³, —SO₂NR³R⁴, —C(O)NR³R⁴,C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀cycloalkylalkyl, —S(O)_(j)(C₁-C₆ alkyl), —S(O)_(j)(CR⁴R⁵)_(m)-aryl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl orheterocyclylalkyl, wherein any of said alkyl, alkenyl, alkynyl,cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyland heterocyclylalkyl portions are optionally substituted with one ormore groups independently selected from oxo (with the proviso that it isnot substituted on an aryl or heteroaryl), halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR⁴SO₂R⁶,—SO₂NR³R⁴, —C(O)R³, —C(O)OR³, —OC(O)R³, —NR⁴C(O)OR⁶, —NR⁴C(O)R³,—C(O)NR³R⁴, —NR³R⁴, —NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —OR³, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl, and wherein said aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl or heterocyclylalkyl rings may be furthersubstituted with one or more groups selected from halogen, hydroxyl,cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl,C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, C₃-C₆heterocycloalkyl, NR³R⁴ and OR³; R³ is hydrogen, trifluoromethyl, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, heterocyclylalkyl, phosphate or an amino acid residue,wherein any of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl andheterocyclylalkyl portions are optionally substituted with one or moregroups independently selected from oxo (with the proviso that it is notsubstituted on an aryl or heteroaryl), halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴,—SO₂NR¹¹R¹², —C(O)R¹¹, C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴, —NR¹¹C(O)R¹²,—C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴, —NR¹¹R¹², —NR¹¹C(O)NR¹²R¹³,—NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl, or R³ and R⁴ together with the atomto which they are attached form a 4 to 10 membered carbocyclic,heteroaryl or heterocyclic ring, wherein any of said carbocyclic,heteroaryl or heterocyclic rings are optionally substituted with one ormore groups independently selected from halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴,—SO₂NR¹¹R¹², —C(O)R¹¹, C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴, —NR¹¹C(O)R¹²,—C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴, —NR¹¹R¹², —NR¹¹C(O)NR¹²R¹³,—NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl; R⁴ and R⁵ independently arehydrogen or C₁-C₆ alkyl, or R⁴ and R⁵ together with the atom to whichthey are attached form a 4 to 10 membered carbocyclic, heteroaryl orheterocyclic ring, wherein said alkyl or any of said carbocyclic,heteroaryl and heterocyclic rings are optionally substituted with one ormore groups independently selected from halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴,—SO₂NR¹¹R¹², —C(O)R¹¹, C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴, —NR¹¹C(O)R¹²,—C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴, —NR¹¹R¹², —NR¹¹C(O)NR¹²R¹³,—NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl; R⁶ is trifluoromethyl, C₁-C₁₀alkyl, C₃-C₁₀ cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl or heterocyclylalkyl, wherein any of said alkyl,cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyland heterocyclylalkyl portions are optionally substituted with one ormore groups independently selected from oxo (with the proviso that it isnot substituted on an aryl or heteroaryl), halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴,—SO₂NR¹¹R¹², —C(O)R¹¹, C(O)OR¹⁴, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴,—NR¹¹C(O)R²—C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴, —NR¹¹R¹²,—NR¹¹C(O)NR¹²R¹³, —NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl, heteroaryl,arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R¹¹,R¹² and R¹³ independently are hydrogen, lower alkyl, lower alkenyl, aryland arylalkyl, and R¹⁴ is lower alkyl, lower alkenyl, aryl andarylalkyl; or any two of R¹¹, R¹², R¹³ or R¹⁴ together with the atom towhich they are attached form a 4 to 10 membered carbocyclic, heteroarylor heterocyclic ring, wherein any of said alkyl, alkenyl, aryl,arylalkyl carbocyclic rings, heteroaryl rings or heterocyclic rings areoptionally substituted with one or more groups independently selectedfrom halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl; m is 0, 1, 2, 3, 4 or 5; and j is0, 1 or
 2. 4. A composition comprising a compound of claim 3 and apharmaceutically acceptable carrier.
 5. The compound of claim 1, whichis:4-(2-Fluoro-4-methylphenylamino)-1,3,8-trimethyl-1H,6H-pyrido[2,3-d]pyridazine-2,5-dione.6. The compound of claim 3, which is:4-(2-Fluoro-4-methylphenylamino)-1,3-dimethyl-7,8-dihydro-1H,6H-pyrido[2,3-d]pyridazine-2,5-dione.